Clinical trial NCT03093428
Conditions: Prostate Cancer
Keywords: Prostate Cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2017-06-09; Completion date: 2025-02-28
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is studying the safety and tolerability of an investigational combination of drugs, radium-223 plus pembrolizumab as a possible treatment for castration-resistant prostate cancer.

The interventions involved in this study are:

* Radium-223
* Pembrolizumab

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

The FDA (the U.S. Food and Drug Administration) has approved radium-223 by itself as a treatment option for the participant's disease.

The FDA has not approved pembrolizumab for the participant's specific disease, but it has been approved for other uses, such as a type of skin cancer called melanoma.

In this research study, the investigators are evaluating the immune response, safety and tolerability of the combination of pembrolizumab (a type of immunotherapy drug) plus radium-223. Pembrolizumab works to block the PD-1 pathway, which plays an important role in lessening the activity of one's immune system to fight cancer. Pembrolizumab is therefore referred to as a PD-1 inhibitor, and acts by stimulating the patient's T cells, which are important immune cells, to attack tumors and treat cancer. Radium-223 targets cancer that exists in the bone directly. Radium-223 binds to minerals in the bone to deliver radiation directly to the cancer that has spread to the bones while limiting damage to the surrounding body tissues. Part of this study is to look at whether the investigators may more effectively control the participant's prostate cancer by combining these drugs. Radium-223 may kill cancer cells and release proteins specific to the tumor. The participant's immune system can then use those proteins to teach the T cells what the cancer looks like, and identify it for attack. Pembrolizumab can increase the number and activity of these immune cells, building a T cell "army" specialized to recognize and attack the cancer. The way these two drugs work on the cancer and the immune system may result in better control of the tumor than just radium-223 alone but needs to be investigated.

Arms: arm 1: * Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose
* Pembrolizumab will be administered intravenously every 3 weeks at a pre-determined dose

Radium-223 will be halted after 3 doses. Once radiographic progressive disease occurs, the last 3 doses of radium will be given. arm 2: \- Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose
Interventions: intervention 1: Radium-223 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Radium-223 is a calcium mimetic that hones in on bone metastases. It binds to new bone stroma and emits alpha particles, which induce double-stranded DNA breaks that result in tumor cell death. intervention 2: Pembrolizumab is a PD-1 inhibitor. Pembrolizumab binds to human PD-1 and blocks the interaction between PD1 and its ligands.

Protocol documents:
Prot_SAP_000.pdf: 
TITLE: A Randomized, Phase II Study Evaluating the Addition of Pembrolizumab (MK-3475) 
to Radium-223 in Metastatic Castration Resistant Prostate Cancer (mCRPC) 
 
 
NCT Number: NCT03093428 
 
 
Protocol Version Date: November 15, 2019 




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SCHEMA 
 
 
 
 
 
*Stratified by serum total alkaline phosphatase <220 or ≥220 and volume of bone 
metastases (high: ≥ 4 bone metastases including one beyond the axial skeleton vs. low: 
<4 bone metastases) 
*Treatment is in terms of weeks not cycles given that radium-223 is given every 4 weeks 
and pembrolizumab is given every 3 weeks.  
*Arm A (radium-223 + pembrolizumab) will have a break in radium-223 dosing after 3 
doses if at least stable disease (SD). Once radiologic progressive disease is demonstrated 
in bone and if no new visceral disease, the last 3 doses of radium will be given. For 
further detail regarding radium-223 dosing, refer to Section 5.4.  
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
SCHEMA .............................................................................................................................2 
1. 
OBJECTIVES ..........................................................................................................5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objectives ...................................................................................................5 
1.3 
Secondary Objectives ...............................................................................................5 
1.4 
Exploratory Objectives ............................................................................................5 
2. 
BACKGROUND .....................................................................................................6 
2.1 
Castration resistant prostate cancer (CRPC) ............................................................6 
2.2 
Study Agents ............................................................................................................6 
2.3 
Rationale for Study ................................................................................................12 
3. 
PARTICIPANT SELECTION ...............................................................................13 
3.1 
Eligibility Criteria ..................................................................................................13 
3.2 
Inclusion Criteria ...................................................................................................13 
3.3 
Exclusion Criteria ..................................................................................................15 
3.4 
Inclusion of Women and Minorities ......................................................................17 
4. 
REGISTRATION PROCEDURES .......................................................................17 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................17 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................18 
5. 
TREATMENT PLAN ............................................................................................18 
5.1 
Treatment Regimen ................................................................................................18 
5.2 
Pre-Treatment Criteria ...........................................................................................20 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................20 
5.4 
Criteria for Taking a Participant Off Protocol Therapy .........................................23 
5.5 
Duration of Follow Up ...........................................................................................26 
5.6 
Criteria for Taking a Participant Off Study ...........................................................26 
5.7 
Clinical Criteria for Early Trial Termination .........................................................27 
6. 
DOSING DELAYS ................................................................................................27 
6.1 
Dose Delay Guidelines for Pembrolizumab ..........................................................28 
6.2 
Dose Modifications for Radium-223 .....................................................................45 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ................46 
7.1 
Expected Toxicities ................................................................................................46 
7.2 
Adverse Event Characteristics ...............................................................................53 
7.3 
Expedited Adverse Event Reporting ......................................................................53 
7.4 
Events of Clinical Interest ......................................................................................55 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) ......................55 
7.6 
Expedited Reporting to Hospital Risk Management .............................................56 
7.7 
Routine Adverse Event Reporting .........................................................................56 


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8. 
PHARMACEUTICAL INFORMATION ..............................................................57 
8.1 
Pembrolizumab4 .....................................................................................................57 
8.2 
Radium-2233 (Xofigo) ...........................................................................................59 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................63 
9.1 
Immune biomarker studies .....................................................................................63 
9.2 
Symptomatic Skeletal Events (SSEs) ....................................................................64 
9.3 
Quality of Life........................................................................................................64 
9.4 
Exploratory Bone Response Criteria .....................................................................65 
9.5 
Mutations in DNA Repair Genes in Prostate Cancer (to be funded by Bayer) .....66 
10. 
STUDY CALENDAR ...........................................................................................69 
11. 
MEASUREMENT OF EFFECT............................................................................72 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................72 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...............................77 
12.1 
Data Reporting .......................................................................................................77 
12.2 
Data Safety Monitoring ..........................................................................................78 
13. 
STATISTICAL CONSIDERATIONS...................................................................78 
13.1 
Study Design/Endpoints.........................................................................................78 
13.2 
Accrual Rate and Study Duration ..........................................................................80 
13.3 
Stratification Factors ..............................................................................................81 
13.4 
Sample size justification ........................................................................................81 
13.5 
Safety Monitoring Plan ..........................................................................................82 
13.6 
Definition of Analysis Populations ........................................................................83 
13.7 
Analysis of Primary Endpoints ..............................................................................83 
13.8 
Analysis of Secondary Endpoints ..........................................................................83 
13.9 
Analysis of Exploratory Clinical Endpoints ..........................................................84 
13.10 Analysis of Exploratory Immune Endpoints..........................................................84 
13.11 Analysis of Exploratory Genomic Endpoints ........................................................86 
13.12 Reporting and Exclusions ......................................................................................87 
14. 
PUBLICATION PLAN .........................................................................................88 
APPENDIX A: Performance Status Criteria .....................................................................88 
APPENDIX B: FACT-P (version 4) ..................................................................................90 
APPENDIX C: Brief Pain Inventory (Short Form) ...........................................................94 
APPENDIX D: Narcotic Analgesic Diary .........................................................................96 
 
 
 
 
 
 
 


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1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a randomized phase II open label study of pembrolizumab, a humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands PD-L1 and PD-L2, in combination with radium-
223. A total of 45 patients with advanced metastatic CRPC will be randomized in a 2:1 
fashion to the combination of pembrolizumab plus radium-223 (Arm A) or to radium-223 
alone (Arm B).  
 
1.2 
Primary Objectives 
 
• To compare differences in immune infiltrating cells (e.g., CD8+, CD4+, T cells) 
in bone biopsy specimens from baseline to 8 weeks on study therapy between the 
treatment arms. 
 
1.3 
Secondary Objective 
 
• To assess the safety and tolerability of combination therapy with pembrolizumab 
plus radium-223 
• To preliminarily investigate the efficacy of the combination of pembrolizumab 
plus radium-223 as evaluated by progression-free survival (PFS) and overall 
survival (OS) 
1.4 
Exploratory Objectives 
 
• To characterize changes in immune cell response and function elicited by radium-
223 with or without pembrolizumab (PD-1 blockade). 
• To evaluate the PSA response including change in PSA and time to PSA 
progression 
• To assess the rate of symptomatic skeletal events (SSEs) and time to SSE in 
patients treated with radium-223 and pembrolizumab.  
• To explore the use of quantitative SPECT/CT for evaluating changes in 
osteoblastic activity on bone scan after radium-223 and pembrolizumab 
• To assess the effect of radium-223 and pembrolizumab on quality of life, pain, 
and analgesic use.  
• To investigate the impact of genomic alterations including those in DNA damage 
repair pathways on clinical outcomes in patients treated with radium-223 with or 
without pembrolizumab.  
• To identify biomarkers of response and to investigate mechanisms of treatment 
resistance through targeted sequencing of cell free DNA at baseline, on therapy, 
and at the time of disease progression. 
 
 


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2. BACKGROUND 
 
2.1 
Castration resistant prostate cancer (CRPC) 
 
Castration resistant prostate cancer (CRPC) is a fatal disease from which nearly 30,000 
men die annually in the United States and over 300,000 worldwide.1  Significant 
improvements in the treatment armamentarium for CRPC have occurred in the last 
several years with the introduction of the next generation androgen biosynthesis inhibitor 
abiraterone, the androgen antagonist enzalutamide, the chemotherapy agent cabazitaxel, 
the therapeutic vaccine, sipuleucel-T, and the novel bone metastasis-homing 
radiotherapeutic, radium-223 dichloride--all of which improve survival. Bone metastases 
occur in over 90% of patients with metastatic CRPC.2  They remain the most frequent 
cause of morbidity and mortality in this disease and incur high treatment-related costs.    
 
2.2 
Study Agents 
 
2.2.1 Radium-223 (Xofigo)3 
 
Radium-223 is a calcium mimetic that hones in on bone metastases due to their high rate 
of bone turnover. It binds to new bone stroma and emits alpha particles, which induce 
double-stranded DNA breaks that result in tumor cell death.2 The short path length of 
alpha particles limits toxicity to surrounding healthy tissue.  Overall, radium-223 is well 
tolerated. The most frequently observed adverse events (AEs) of any grade in the phase 3 
study were anemia (31%), thrombocytopenia (12%), constipation (18%), diarrhea (25%), 
nausea (36%), vomiting (18%), fatigue (26%), peripheral edema (13%), anorexia (17%), 
and bone pain (50%). Compared to placebo, radium-223 increased median overall 
survival from 11.3 months to 14.9 months and reduced the risk of death by 30% (HR: 
0.70; 95%CI: 0.58-0.83; p<0.001).2 Radium-223 has also been shown to significantly 
increase the median time to the first symptomatic skeletal event (15.6 vs. 9.8 months) and 
the time to increase in total alkaline phosphatase (7.4 vs. 3.8 mo.) Compared to placebo, 
it elicited a higher rate of normalization of serum alkaline phosphatase (34 vs. 1%) and 
PSA declines ≥30% (16% vs. 6%).  
 
Description 
Radium Ra 223 dichloride is an alpha particle-emitting radiopharmaceutical. 
 
Radium-223 is supplied as a clear, colorless, isotonic, and sterile solution to be 
administered intravenously with pH between 6 and 8.  Each milliliter of solution 
contains 1,000 kBq radium-223 dichloride (27 microcurie), corresponding to 0.53 ng 
radium­223, at the reference date. Radium is present in the solution as a free divalent 
cation. 
 
Each vial contains 6 mL of solution (6,000 kBq (162 microcurie) radium-223 
dichloride at the reference date). The inactive ingredients are 6.3 mg/mL sodium 
chloride USP (tonicity agent), 7.2 mg/mL sodium citrate USP (for pH adjustment), 


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0.2 mg/mL hydrochloric acid USP (for pH adjustment), and water for injection 
USP. 
 
The molecular weight of radium-223 dichloride, 223RaCl2, is 293.9 g/mol. 
 
Radium-223 has a half-life of 11.4 days. The specific activity of radium-223 is 1.9 MBq 
(51.4 microcurie)/ng. 
 
The six-stage-decay of radium-223 to stable lead-207 occurs via short-lived daughters, 
and is accompanied predominantly by alpha emissions. There are also beta and gamma 
emissions with different energies and emission probabilities. The fraction of energy 
emitted from radium-223 and its daughters as alpha-particles is 95.3% (energy range of 5 
- 7.5 MeV). The fraction emitted as beta-particles is 3.6% (average energies are 0.445 
MeV and 0.492 MeV), and the fraction emitted as gamma-radiation is 1.1% (energy 
range of 0.01 - 1.27 MeV). 
 
Mechanism of action  
The active moiety of radium-223 is the alpha particle-emitting isotope radium-223 (as 
radium Ra 223 dichloride), which mimics calcium and forms complexes with the bone 
mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The 
high linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high 
frequency of double-strand DNA breaks in adjacent cells, resulting in an anti-tumor effect 
on bone metastases. The alpha particle range from radium-223 dichloride is less than 100 
micrometers (less than 10 cell diameters), which limits damage to the surrounding normal 
tissue. 
 
Pharmacodynamics 
Compared with placebo, there was a significant difference in favor of radium-223 for all 
five serum biomarkers for bone turnover studied in a phase 2 randomized study (bone 
formation markers: bone alkaline phosphatase [ALP], total ALP and procollagen I N 
propeptide [PINP], bone resorption markers: C-terminal crosslinking telopeptide of type I 
collagen [S-CTX-I] and type I collagen crosslinked C-telopeptide [ICTP]). 
 
Pharmacokinetics: Elimination 
The whole body measurements indicated that approximately 63% of the administered 
radioactivity was excreted from the body within 7 days after injection (after correcting 
for decay). Fecal excretion is the major route of elimination from the body. At 48 hours 
after injection, the cumulative fecal excretion was 13% (range 0 - 34%), and the 
cumulative urine excretion was 2% (range 1 - 5%). There was no evidence of hepato-
biliary excretion based on imaging data. 
 
The rate of elimination of radium-223 dichloride from the gastrointestinal tract is 
influenced by the high variability in intestinal transit rates across the population. Patients 
with a slower intestinal transit rate could potentially receive a higher intestinal radiation 
exposure. It is not known whether this will result in increased gastrointestinal toxicity. 
 


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Summary of Clinical Experience 
The efficacy and safety of radium-223 were evaluated in a double-blind, randomized, 
placebo-controlled phase 3 clinical trial of patients with castration-resistant prostate 
cancer with symptomatic bone metastases. Patients with visceral metastases and 
malignant lymphadenopathy exceeding 3 cm were excluded. The primary efficacy 
endpoint was overall survival. A key secondary efficacy endpoint was time to first 
symptomatic skeletal event (SSE) defined as external beam radiation therapy (EBRT) to 
relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of 
spinal cord compression, or tumor-related orthopedic surgical intervention. There were no 
scheduled radiographic assessments performed on study. All patients were to continue 
androgen deprivation therapy. At the cut-off date of the pre-planned interim analysis, a 
total of 809 patients had been randomized 2:1 to receive radium-223 50 kBq (1.35 
microcurie)/kg intravenously every 4 weeks for 6 cycles (n = 541) plus best standard of 
care or matching placebo plus best standard of care (n = 268). Best standard of care 
included local EBRT, corticosteroids, antiandrogens, estrogens, estramustine or 
ketoconazole. Therapy was continued until unacceptable toxicity or initiation of cytotoxic 
chemotherapy, other systemic radioisotope, hemi-body EBRT or other investigational 
drug. Patients with Crohn’s disease, ulcerative colitis, prior hemibody radiation or 
untreated imminent spinal cord compression were excluded from the study. In patients 
with bone fractures, orthopedic stabilization was performed before starting or resuming 
treatment with radium-223. 
 
The following patient demographics and baseline disease characteristics were balanced 
between the arms. The median age was 71 (range 44-94) with a racial distribution of 94% 
Caucasian, 4% Asian, 2% Black and <1% Other. Patients were enrolled predominantly 
from Europe (85%) with 4% of patients enrolled from North America. ECOG 
performance status was 0-1 in 86% of patients. Eighty-five percent of patients had 6 or 
more bone scan lesions and of those 40% had > 20 lesions or a superscan. Opiate pain 
medications were used for cancer-related pain in 54% of patients, non-opiate pain 
medications in 44% of patients and no pain medications in 2% of patients. Patients were 
stratified by baseline ALP, bisphosphonate use, and prior docetaxel exposure. Prior 
bisphosphonates were used by 41% of patients and 58% had received prior docetaxel. 
During the treatment period, 83% of radium-223 patients and 82% of placebo patients 
received gonadotropin-releasing hormone agonists and 21% of radium-223 patients and 
34% of placebo patients received concomitant antiandrogens. Use of systemic steroids 
(41%) and bisphosphonates (40%) was balanced between the arms. 
 
The pre-specified interim analysis of overall survival revealed a statistically significant 
improvement in patients receiving radium-223 plus best standard of care compared with 
patients receiving placebo plus best standard of care. An exploratory updated overall 
survival analysis performed before patient crossover with an additional 214 events 
resulted in findings consistent with the interim analysis (Table 1). 
 
 


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Table 1: Analysis Data of Radium-223 (Xofigo) plus best standard of care vs. 
Placebo plus best standard of care 
 
Summary of Adverse Events 
 
The most common adverse reactions (≥ 10%) in patients receiving radium-223 were 
nausea, diarrhea, vomiting, and peripheral edema. Grade 3 and 4 adverse events were 
reported among 57% of radium-223-treated patients and 63% of placebo treated patients. 
The most common hematologic laboratory abnormalities in radium-223-treated patients 
(≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. 
Treatment discontinuations due to adverse events occurred in 17% of patients who 
received radium-223 and 21% of patients who received placebo. The most common 
hematologic laboratory abnormalities leading to discontinuation for radium-223 were 
anemia (2%) and thrombocytopenia (2%).  
 


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2.2.2 Pembrolizumab  (MK-3475, Keytruda)4,5 
 
Despite the confirmed efficacy of radium-223 in CRPC, resistance is universal. Novel 
tolerable combinations are imperative to improve outcomes in CRPC.  The last several 
years have witnessed a resurgence of interest in mobilizing the immune system to combat 
cancer.  The PD-1 pathway is a promising target.  PD-1 is an inhibitory receptor 
expressed on activated T and B lymphocytes. It regulates T cell antigen-specific signaling 
and modulates T cell activation, inactivation, and survival.6 Interaction with its two 
known ligands, PD-L1 and PD-L2, inhibit T cell activation, apoptosis, and memory 
responses.7,8 Tumor cells can express PD-L1 and other immunoinhibitory ligands, which 
may attenuate the effects of antitumor cytotoxic T cells and stymie production of 
essential immune stimulating cytokines.9-11 PD-L1 may be constitutively expressed on 
tumor cells or can arise as a consequence of adaptive immunity in response to stressors 
such as the cytotoxic interferon-γ secreted by TILs in the tumor microenvironment and 
treatment with other anticancer agents.12-18  
 
Blocking antibodies, such as pembrolizumab have been developed to counteract this 
tumor evasion mechanism. Pembrolizumab is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.  KeytrudaTM 
(pembrolizumab) has recently been approved in the United Stated for the treatment of 
patients with unresectable or metastatic melanoma and disease progression following 
ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 
In a phase 1 study of multiple solid tumors, pembrolizumab has demonstrated tolerability 
and preliminary efficacy. The most frequent AEs were fatigue, asthenia, fever, chills, 
myalgias, diarrhea, rash, and pruritus.19,20 While PD-L1 has not been shown to be 
upregulated in the majority of prostate cancer cases sampled,21 data from work with other 
PD-1 pathway blocking antibodies such as Genentech’s anti-PD-L1 molecule 
MDPL3280A demonstrate that the PD-L1 expression on the tumor infiltrating immune 
cells is also of importance and correlates with a higher chance of response to the drug.  
 
Preclinical and Clinical Trial Data: 
Refer to the Investigator’s Brochure for Preclinical and Clinical data for full details.5 
Clinical Summary of Results 
As of 18-Oct-2013, 1,000 patients have been treated with MK-3475 at several 
dose-schedules, including 10 mg/kg every 2 weeks.  MK-3475 has been generally well 
tolerated, as expected based on preclinical findings and other anti-PD-1 monoclonal 
antibodies.  As of 18-Oct-2013 no serious infusions reactions have been reported in 
PN001.  Less than 1% of patients thus far assayed had confirmed positive ADA 
samples and among these, no or no clear impact on exposure has been observed. There 
is no contraindication to further clinical investigation with MK-3475.  
 
Pharmacokinetics were as expected, based on MK-3475 being an IgG mAb and 
based on preclinical data, which support dosing once every 2 or 3 weeks.  
 


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MK-3475 monotherapy induces an ORR of 25-27% in patients with ipilimumab- 
exposed melanoma by central independent RECIST and oncology 
review/investigator assessed irRC, respectively.   MK-3475 monotherapy induces an 
ORR of 39%/43% in patients with ipilimumab-naive melanoma by central independent 
RECIST and oncology review/investigator assessed irRC, respectively.  These responses 
are remarkably durable. The preliminary 1-year survival rate for patients, many of 
whom have had multiple therapies, including ipilimumab, who receive MK-3475 is 
81%.  MK-3475 monotherapy induces an ORR of 21%/24% in patients with 
previously-treated NSCLC by central independent RECIST/investigator assessed 
irRC, respectively, with these responses also remarkably durable.    
 
Preliminary data suggest higher levels of PD-L1 expression in tumors of NSCLC 
are associated with increased activity (ORR 67% by investigator assessed 
irRC/57% by central independent RECIST); additional data are required to define 
the optimal PD-L1 cut point.   
 
The most commonly reported treatment emergent AEs experienced were fatigue 
(43.8%), nausea (26.7%), cough (25.3%), pruritus (24.6%), diarrhea (22.3%) and rash 
(21.5%).   Immune-related adverse events were reported in 21.4% of melanoma 
patients; most of these events (15.8%) were considered drug-related by the investigator.  
The most commonly reported, immune-related adverse events across the dose-schedules 
were rash (3.2%), pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia 
(2.2%), diarrhea (2.2%), and pneumonitis (1.9%).  
 
Rationale for Dose Selection: 
 
An open-label Phase I trial (Protocol 001) is evaluating the safety and clinical activity of 
single agent MK-3475.  The dose escalation portion of this trial evaluated three dose levels, 
1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting 
toxicities were observed.  This first in human study of MK-3475 showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 
mg/kg and 10 mg/kg Q2W).  No maximally tolerated dose (MTD) has been identified to 
date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule 
utilized in Cohorts A, B, C and D of this protocol to test for initial tumor activity.  Recent 
data from other clinical studies within the MK-3475 program has shown that a lower dose 
of MK-3475 and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (see IB).  Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days).  
This early PK and pharmacodynamic data provides scientific rationale for testing a Q2W 
and Q3W dosing schedule.   
 


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A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the 
range observed for other antibodies and would support both body weight normalized 
dosing or a fixed dose across all body weights.  MK-3475 has been found to have a wide 
therapeutic range based on the melanoma indication.  The differences in exposure for a 200 
mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for MK-
3475 in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 
mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed 
that there was no significant impact of tumor burden on exposure. In addition, exposure 
was similar between the NSCLC and melanoma indications. Therefore, there are no 
anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed 
at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the 
assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
 
2.3 
Rationale for Study 
 
We posit that tumor cell killing with radium-223 will release tumor-associated antigens 
(TAAs). Dendritic cells will take up these antigens, process them, and present them to 
naïve T cells. These T cells will mature into tumor-specific effector cells that will 
proliferate and ultimately hone in on the cancer. The addition of PD-1 blockade may 
reverse any potential anergy of these PD-1+ infiltrating anti-tumor immune cells. Tumor 
heterogeneity and the dynamic nature of PD-L1 expression on tumor cells and PD-1 and 
PD-L1 expression on immune cells in the tumor microenvironment provides further 
rationale for this approach even in the absence of high PD-L1 expression upfront. 


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Theoretically, if the TAAs released by radium-induced tumor killing stimulate higher 
numbers of tumor specific T cells, this may induce adaptive upregulation of PD-L1 by the 
tumor in response to IFN-γ secreted by these cells.  
 
While 6 treatments of radium-223 is the standard regimen that was studied in the 
registration clinical trial, there is actually no data on what the correct number of doses for 
treatment is, nor is there any evidence that the schedule must be maintained for 
efficacy.  Indeed, when administering standard of care radium-223, treatment can be held 
or discontinued because of inadequate blood counts, particularly during later cycles of 
treatment. Because pembrolizumab is dependent on lymphocytes to mediate anti-tumor 
responses, we proposed this modified schedule of radium-223.  All patients will receive 
the planned 6 doses if counts allow, but the investigational cohort will have a delay in the 
final three radium-223 doses, so that any treatment-induced myelosuppression does not 
impact the efficacy of pembrolizumab.  Radiation therapy has been described to influence 
the T cell repertoire when given with checkpoint blockade. 22 Modulation of circulating 
PD-1+ CD8 T cells has been seen after a single treatment of radium-223 (Kim et al. GU 
ASCO 2016).  Thus, we assert that an empirically defined 6 doses of radium-223 is not 
needed to see immune modulation. 
 
While our treatment armamentarium has significantly improved in the last few years with 
next generation chemotherapeutic and antiandrogen-targeted therapies in CRPC, 
resistance is universal. Harnessing the patient’s immune system to enhance proven 
effective therapies like radium-223 has great potential to make significant inroads in the 
fight against CRPC and impact the lives of the more than 300,000 patients that die from 
CRPC globally. 
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
All screening assessments must be completed within 42 days prior to the date of 
treatment initiation.   
 
3.2 
Inclusion Criteria  
 
• Histologically confirmed adenocarcinoma of the prostate 
• Castration-resistant prostate cancer requires the following 3 criteria:  
− Progression after surgical castration or on GnRH agonist or antagonist 
− 
A castrate level of testosterone (<50ng/dL) 
− 
Prostate cancer progression documented by PSA rise or bone progression 
according to PCWG223 
• 
There is no limit to number of prior therapies 
• 
Metastatic disease by bone scan  
• 
Age ≥18 years 


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• 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(Appendix A) 
• 
Be willing to undergo a core or excisional biopsy of a bone metastasis prior to 
study drug initiation for tumor tissue. Newly-obtained is defined as a specimen 
obtained up to 12 weeks (84 days) prior to initiation of treatment on Day 1. Bone 
biopsy can have been done prior to screening; archival specimens of bone 
metastasis are permitted if done for other purpose and available.  
o If biopsy is non-diagnostic, patient must undergo repeat biopsy as proof of 
tumor tissue by pathology review. Proof of tumor specimen is required for 
eligibility. If 2nd biopsy is non-diagnostic, the patient may enroll as good 
faith effort.  
• 
Be willing to undergo a second core or excisional biopsy of a bone metastasis on 
therapy (approximately after 8 weeks of study therapy or after 2 doses of radium-
223 if delays have occurred).   
• 
Demonstrate adequate organ function as defined in the Table below, all screening 
labs for eligibility should be performed within 42 days prior to treatment 
initiation.   
 
Table 2:  Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L; transfusions permitted 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X institutional upper limit of normal (ULN) OR 
 
≥30 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X institutional ULN OR 
 
Direct bilirubin ≤ institutional ULN for subjects with total 
bilirubin levels > 1.5 institutional ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X institutional ULN   
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X institutional ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5 X institutional ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
• The effects of radium-223 and pembrolizumab on the developing human fetus are 
unknown.  For this reason, men must agree to use adequate contraception. 
Specifically, they must agree to use a condom (even men with vasectomies) and 
another effective method of birth control if he is having sex with a woman of 
childbearing potential or agree to use a condom if he is having sex with a woman 
who is pregnant while on study drug and for 120 days (4 months) following the 


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last dose of study drug. They must also agree not to donate sperm during the study 
and for 4 months after receiving the last dose of study drug. 
• Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.3 
Exclusion Criteria 
 
• Pathology consistent with majority of specimen having small cell carcinoma of 
the prostate (prostate cancer with other neuroendocrine features is acceptable). 
• Prior treatment with radium-223 
• Prior treatment with a PD-1, PD-L1, or PD-L2 blocking therapy 
• Evidence of nodal disease greater than or equal to 15 mm in short axis as these 
findings are concerning for metastases that would not be targeted with radium-
223 alone (Arm B). However, lymph nodes with short axis measurements 
between 1.5-3cm that have not enlarged more than 5mm (to account for reader 
variability) over the last 6 months and which are not inducing symptoms, causing 
obstruction, or in the opinion of the investigator pose a risk of impending 
obstruction of any structures, will be allowed. 
• Pulmonary nodules > 10 mm 
o Pulmonary nodules > 10mm that have been stable for >6 months and are 
not clearly metastatic disease per the treating investigator are permitted  
• Soft tissue components of bone metastases ≥ 1.0 cm in longest axis 
o Soft tissue components of bone metastases < 1.0 cm that have been stable 
for >6 months (must not have enlarged > 5mm) are permitted 
• Soft tissue lesions ≥ 1.0 cm in longest axis 
o Soft tissue lesions < 1.0 cm that have been stable for > 6 months (must not 
have enlarged > 5mm) are permitted. 
• If present, primary disease in the prostate must be stable for > 6 months (defined 
as no growth > 5mm) 
• Evidence of local recurrence in the prostate bed  
• Evidence of liver metastases or visceral disease 
• Has a diagnosis of immunodeficiency  
• Patients requiring systemic steroid therapy with >10mg prednisone or its 
equivalent daily. Patients receiving systemic steroid therapy for non-autoimmune 
processes (e.g., COPD, adrenal replacement therapy) are permitted if on stable 
dose and asymptomatic. 
 
• Has a known history of active TB (Bacillus Tuberculosis) 
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to agents administered more than 4 weeks earlier. 
• Has had prior systemic therapy (exception: GnRH agonist or antagonist) or 
radiation therapy for prostate cancer within 2 weeks prior to study Day 1.  There 
must be at least a 2 week washout period from last dose of any prior systemic or 
radiation therapy for prostate cancer prior to Day 1 of study treatment (including 


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nonsteroidal antiandrogens). Screening may commence during this washout 
window.  
• Any patient who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events or complications due to a previously administered systemic agent, 
radiation therapy, or major surgery. 
o Exceptions:   
 Subjects with ≤ Grade 2 neuropathy, hot flashes, or hypertension 
may qualify for the study if all other eligibility criteria met. 
 Other toxicity or complications that are deemed by the treating 
investigator as not clinically significant (e.g., urinary incontinence 
from past prostatectomy, peripheral edema from past taxane 
therapy) 
• Diethylstilbestrol, estrogens, saw palmetto, or other preparations that are known 
to have possible endocrine effects on prostate cancer that have been started within 
the past 8 weeks, as they may affect PSA levels or response. These are allowed if 
the patient has been on a stable dose for at least 8 weeks prior to C1D1. 
• Receiving other investigational agents 
• History of allergic reactions to compounds with similar biologic or chemical 
composition to pembrolizumab or radium-223 
• Has a known additional malignancy that is progressing or requires active 
treatment. Exceptions include basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that is planned for curative therapy. 
• Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least 
four weeks prior to the first dose of trial treatment and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain metastases, 
and are not using steroids for at least 7 days prior to trial treatment.  This 
exception does not include carcinomatous meningitis, which is excluded 
regardless of clinical stability.   
• 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.  
• Has known history of, or any evidence of active, non-infectious pneumonitis. A 
history of radiation pneumonitis which is asymptomatic with no signs of active 
process is allowed. 
• Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best interest 
of the subject to participate, in the opinion of the treating investigator.   
• Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies).  HIV-positive participants on combination antiretroviral therapy are 


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ineligible because of the potential for pharmacokinetic interactions with 
pembrolizumab.  In addition, these participants are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.  Appropriate studies 
will be undertaken in participants receiving combination antiretroviral therapy 
when indicated. 
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA is detected). 
• Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated 
flu vaccines and are allowed; however intranasal influenza vaccines (e.g., 
Flu-Mist®) are live attenuated vaccines, and are not allowed. 
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, severe or unstable angina, myocardial infarction, symptomatic 
congestive heart failure (defined as New York Heart Association Grade II or 
greater), arterial or venous thromboembolic events (e.g., pulmonary embolism, 
cerebrovascular accident including transient ischemic attacks) or clinically 
significant ventricular arrhythmias within 6 months prior to randomization; or 
significant vascular disease (e.g., aortic aneurysm, aortic dissection), symptomatic 
peripheral vascular disease 
• Evidence of QTc prolongation as defined as QTcF > 470 ms (per Fridericia’s 
formula) 
• Inability to comply with study and/or follow-up procedures 
 
3.4 
Inclusion of Women and Minorities 
 
Men of all races and ethnic groups are eligible for this trial. 
 
Women are not eligible for this trial as they do not have prostates and as such do not get 
prostate cancer. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System 
(CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. Any 
participant not registered to the protocol before protocol therapy begins will be 
considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will 
complete the protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a 
participant does not receive protocol therapy following registration, the participant’s 


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registration on the study must be canceled. Registration cancellations must be made in 
OnCore as soon as possible. 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) must be followed.   
 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
Following registration, participants will be randomized in a 2:1 ratio to either Arm A: a 
combination of Radium-223 and pembrolizumab or Arm B: Radium-223 alone. 
 
Patients will be stratified based on: 
 
• Baseline alkaline phosphatase <220 or ≥220 
• Volume of bone metastases (high: ≥ 4 bone metastases including one beyond 
the axial skeleton vs. low: <4 bone metastases) 
-Based on CHAARTED (ECOG 3805) criteria24    
 
Given the varied dosing of the two agents, we will refer to weeks on study instead of 
cycles.  
 
Radium-223 55kBq/kg (1.49µCi)/kg will be administered intravenously (IV) slowly over 
1 minute every 4 weeks for a maximum of 6 doses.  Weight used for dosing should be 
based on institutional standards. Radium-223 will be administered in the nuclear 
medicine suite at DFCI and at the corresponding department for participating 
investigational sites. 
  
Pembrolizumab will be given only to patients randomized to the investigational arm 
(Arm A). Pembrolizumab will be given at a dose of 200mg intravenously every 3 weeks. 
It will be administered in the Yawkey Infusion Center at DFCI and at the corresponding 
department for participating investigational sites. 
 
Treatment with both agents will be administered on an outpatient basis.  Reported 
adverse events and potential risks are described in Section 7. No investigational or 
commercial agents or therapies other than those described below may be administered 
with the intent to treat the participant's prostate cancer. 
 
No dose modifications will be made for either agent.  If study agents are held for more 
than 12 weeks (for pembrolizumab) or 8 weeks (for Radium-223) due to study drug-
related toxicity, the patient should be discontinued from the offending agent. Patients 
may continue on either agent alone if tolerating. 


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Table 3: ARM A - Combination Investigational Arm 
Agent 
Premedication 
Dose 
Route 
Schedule 
Pembrolizumab 
 
None unless 
prior reaction; 
(see Table 6) 
200mg 
(diluted 
per 
institution
al 
guidelines
/package 
insert)  
IV 30 minutes  
 -5 min/+ 10 
min 
Every 3 weeks (21 +/-3 
days) 
 
*Should be given prior 
to radium on days 
when they are given 
together. 
Radium-223 
None 
55kBq/kg 
(1.49µCi)/
kg 
 
IV over 1 
minute or 
longer per 
institutional 
standards 
Every 4 weeks (28 +/- 
7 days) for 3 doses 
followed by a break 
until radiologic disease 
progression. Then the 
last 3 doses will be 
given every 4 weeks 
(28 +/-7 days) 
 
*Lupron/GnRH agonist or antagonist should be continued unless intolerable or 
discontinued for other safety reasons. 
**Adhering to the schedule should be encouraged, and the 7 day window should not be 
utilized to give pembrolizumab and radium-223 on the same day for scheduling 
convenience.  
 
Order of Administration – In the combination arm, pembrolizumab should be 
administered prior to radium-223 on days when both are given on the same day. No 
minimum time is required between the administration of drugs.  
 
 
Table 4: ARM B - Control Arm 
Agent 
Premedication  
Dose 
Route 
Schedule 
Radium-223 
None 
 
55kBq/kg 
(1.49µCi)/kg 
IV over 1 minute 
or longer per 
institutional 
standards 
Every 4 
weeks (28 
+/- 7 days) 
for 6 doses 
*Lupron/GnRH agonist or antagonist should be continued unless intolerable or 
discontinued for other safety reasons. 
 
Trial treatment should begin on the day of randomization or within 7 days after 
randomization. 
 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution (Section 8.1). 
 


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5.2 
Pre-Treatment Criteria 
 
5.2.1 Cycle 1, Day 1 
 
Pre-Treatment Criteria for C1D1. D1 dosing criteria of subsequent cycles (2 and 
beyond) should follow Section 6 guidelines: 
 
C1D1 labs must meet the following criteria prior to treatment but do not need to 
re-meet eligibility criteria: 
• Absolute neutrophil count ≥1,500/mcL 
• Hemoglobin ≥10g/dL  
*transfusions and/or erythropoietin supplementation permitted 
• Platelets ≥100,000/mcL 
• Total bilirubin ≤1.5x institution’s upper limit of normal (unless known 
Gilbert’s syndrome) 
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal ULN 
• Creatinine clearance ≥30 mL/min/1.73 m2 for participants with creatinine 
levels above institutional ULN. (Note: creatinine clearance should be 
calculated per institutional standard) 
• If screening assessments have been done within 72 hrs prior to C1D1, they 
may be used in lieu of repeat C1D1 assessments (e.g., labs, ECOG, exam). 
 
5.2.2 Subsequent Cycles  
 
• Day 1 complete metabolic panel and complete blood count (CBC) with 
differential must be reviewed by study staff prior to treatment to ensure they 
meet criteria as detailed in Section 6 
o Other labs such as thyroid function tests that may take longer to result 
do not have to be reviewed prior to the dose 
• CBC with differential should be obtained prior to each dose of radium-223 or 
pembrolizumab and doses given only if eligible per guidelines in Section 6 
• Day 1 assessments may be performed within 72 hours prior to study drug 
administration. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
If there is a clinical indication for medications or vaccinations specifically prohibited in 
the exclusion criteria, discontinuation from trial therapy or vaccination may be required.  
The investigator should discuss any questions regarding the use of these agents with the 
PI who will discuss with the Merck Clinical team as needed.  The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the subject's primary 
treating physician. 
 
 


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5.3.1 Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care.  All concomitant medication will be recorded on the case report form 
(CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
Treatment with non-conventional therapies and vitamin/mineral supplements is 
acceptable provided that, in the opinion of the investigator, such treatment will not 
interfere with study treatment and the trial endpoints. If they do, the subject may need to 
be discontinued from the trial and this should be discussed with the PI. 
 
Subjects may receive standard of care for any underlying illness provided therapy does 
not interfere with study treatment and the trial endpoints. 
 
In the event of neutropenia, anemia, or thrombocytopenia, subjects may receive 
appropriate supportive care (such as transfusion, biologic response modifiers such as G-
CSF or GM-CSF, prophylactic antibiotics, antifungals and/or antivirals, hematopoietic 
growth factors).  
 
If surgery is required during study drug treatment, the surgeon needs to be notified that 
the patient has been treated with a radioactive product and adequate precautions for 
radioactive protection should be applied during the surgical procedure.  The patient 
should continue with study treatment if considered safe in the treating investigator's 
opinion. 
 
Radium-223 can be administered with concurrent osteoclast-targeting agents including 
bisphosphonates and denosumab if the patient is already on them for > 28 days prior to 
Day 1 of study treatment. These agents should not be started while the patient is on the 
study unless needed for the management of hypercalcemia or a skeletal-related event. If a 
patient has already been receiving an osteoclast-targeting agent prior to study entry, it 
may be continued or suspended during concurrent administration of radium-223 at the 
discretion of the treating investigator. 
 
Consideration should be given to using concomitant bone health agents such as 
bisphosphonates on either arm of the study. Patients receiving bisphosphonates, 
denosumab, zoledronic acid or similar therapy prior to randomization may be maintained 
on this therapy during the study. Bisphosphonates denosumab, zoledronic acid or similar 
therapy can be stopped or started at the discretion of the investigator throughout the 
study.   


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22 
 
 
5.3.2 Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Treatment 
Phase of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy other than radium-223 
o Note:  Patients may undergo palliative radiation to combat clinical (e.g., 
symptomatic) progression while on study if (1) the patient was achieving 
overall clinical benefit according to the treating investigator; and (2) the 
Principal Investigator has determined it acceptable to do so. Study drugs 
should be continued during radiation unless discussed with the PI that 
holding is in the best interest of the patient (e.g., concurrent toxicity 
concerns). 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: intranasal influenza, measles, mumps, rubella, varicella/zoster, 
yellow fever, rabies, BCG, and typhoid vaccine.  
• Systemic glucocorticoids are prohibited, with the following exceptions: 
o To modulate symptoms from an event of clinical interest (ECI) of suspected 
immunologic etiology while on study.   
o Baseline systemic steroids ≤10mg of prednisone or its equivalent for non-
autoimmune processes (e.g., COPD, physiologic replacement doses) if on 
stable dose and asymptomatic. 
• Diethylstilbestrol, estrogens, saw palmetto or other preparations thought to have 
endocrine effects on prostate cancer are allowed if the patient has been on a stable 
dose for at least 8 weeks prior to C1D1. 
 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describe other medications, which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.3.3 Supportive Care Medications 
 


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• Drugs needed for supportive care such as anti-emetics are permitted  
 
• Steroids for nausea: dexamethasone, prednisone and other systemic steroids 
should be avoided, if possible, due to their immunosuppressive properties. If 
clinically indicated, steroid dose should not exceed 10mg of prednisone per day 
or equivalent. 
 
• Subjects should receive appropriate supportive care measures as deemed necessary by 
the treating investigator. Suggested supportive care measures for the management of 
adverse events with potential immunologic etiology are outlined below. Where 
appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such 
as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. These treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab. If not thought 
related, care is per investigator discretion. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event. 
 
5.4 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression 
and tolerance. In the absence of treatment delays due to adverse event(s) or the scheduled 
break after the first 3 doses of radium-223 in arm A, treatment may continue for up to a 
total of 6 doses of radium-223 and up to 35 doses (24 months) of pembrolizumab if 
achieving clinical benefit and tolerating or until one of the following criteria applies: 
 
• Disease progression 
 
• 
Arm A:  
 
- 
After 3 months on study therapy (generally week 12 re-staging scans) 
 
• 
If the patient has stable disease or better, they will start on a 
radium-223 break, but continue on pembrolizumab.  
• 
If there have been treatment delays, the break should not 
commence until at least 3 doses of radium are given unless the 
radium-223 is deemed intolerable/toxic. 
If pembrolizumab has been discontinued due to toxicity despite 
stable disease or better, radium-223 will be continued without a 
break, and study assessments will be conducted on the same 
schedule as Arm B. 


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24 
 
• 
Due to the intricacies of assessing response/progression in bone 
only disease, in cases where the treating investigator feels the 
patient is clinically benefiting from the radium-223 and that a 
break would be harmful to disease control, omission of the 
break will be permitted on a case-by-case basis after discussion 
with the PI. These patients will be continued on the radium-223 
every month without break as is standard of care. Study 
assessments during combination therapy will continue per the 
required data table in Arm A. Scans will continue to adhere to 
the study schedule (every 12 weeks). Alternatively, the patient 
or clinician may choose to stop study therapy and proceed with 
alternative systemic therapies at their discretion.  
 
• 
If 2 or more new bone lesions (“unconfirmed progression”) are 
present on initial scans and the patient has received all 3 initial 
doses, radium-223 should be continued until reassessment with 
confirmatory scans ≥ 6 weeks. 
 
• 
If “unconfirmed progression” of nodal disease occurs, but no new 
visceral disease, the patient may continue on pembrolizumab and 
radium-223 until reassessment with confirmatory scans ≥ 6 weeks 
or be discontinued per treating investigator’s discretion. 
 
• 
For patients with unconfirmed bone or nodal progression who 
continue on study therapy after initial restaging scans (~12 weeks), 
if subsequent scans (at least ≥ 6 weeks from initial scans) show: 
• 
The disease has stabilized or improved: they may continue on 
study therapy until disease progression or until 
intolerability/toxicity precludes further administration. 
• 
Continued radiologic progression per RECIST v1.1 or 
PCWG2: the patient should be discontinued from study 
therapy. If the treating investigator believes the patient is 
clinically benefiting, continuation of one or both study drugs 
may be permitted upon discussion with PI. 
 
• 
If there is evidence of new visceral disease at any point, the patient 
should be discontinued from both agents. 
 
- 
For all subsequent scans of patient who commence on radium-223 
break: 
 
• 
If the patient continues to have stable disease or better, they will 
continue on pembrolizumab alone.  
 
• 
If the patient went on radium-223 break, it may be restarted: 
• 
Whenever the patient meets progressive disease criteria per 


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protocol as long as there is no new visceral disease. No 
confirmatory scans are required unless the treating investigator 
prefers to wait to confirm before restarting. The rationale to 
allow restarting of radium-223 in patients who are progressing 
in the nodes is the possible role of radium-223 as an immune 
modulator that may help stimulate the immune response to 
pembrolizumab. 
• 
In cases where treating investigator feels that patient would 
clinically benefit from restarting radium-223, even though not 
technically progressing by RECIST v 1.1 or PCWG2, will be 
discussed and permitted only on a case-by-case basis with the 
PI. 
• 
If the patient meets protocol criteria for disease progression on 
the next scheduled scans after restarting radium-223 (and has 
received at least 2 more doses of radium-223), they should be 
discontinued from study therapy. If they do not meet these 
criteria or treating investigator believes they are clinically 
benefiting, they may be permitted to continue on a case-by-
case basis after discussion with the PI. Similarly, if treating 
physician feels the patient is clinically progressing prior to 2 
more doses of radium-223, the patient can be discontinued 
from study therapy. 
 
• 
If patient has signs of new visceral disease at any time meeting 
RECIST v1.1 criteria, they will be discontinued from study 
therapy.  
 
- 
For subsequent scans of  patients who do not commence on radium-
223 break: 
 
• 
If the patient continues to have stable disease or better, they will 
continue on combination study therapy. 
 
• 
If scans show progressive disease per protocol criteria, they should 
discontinue therapy. In cases where treating investigator feels that 
the patient would clinically benefit from continuing study therapy 
even though they are technically progressing by RECIST v1.1 or 
PCWG2, continuation will be discussed on a case-by-case basis 
with the PI. 
 
• 
Arm B 
 
- 
Continue on radium-223 until the patient meets protocol criteria for 
disease progression, up to a maximum of 6 doses.  
 
• Intercurrent illness that prevents further administration of treatment 


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26 
 
 
• Unacceptable adverse event(s) 
 
• Participant demonstrates an inability or unwillingness to comply with the 
documentation requirements 
 
• Participant decides to withdraw from the protocol therapy 
 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. Note: 24 months of study 
medication is calculated from the date of first dose. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  
The reason for removal from protocol therapy, and the date the participant was removed, 
must be documented in the case report form (CRF). Alternative care options will be 
discussed with the participant. 
 
An ODQ Treatment Ended/Off Study Form will be completed when a participant is 
removed from protocol therapy. This form can be found on the ODQ website or obtained 
from the ODQ registration staff. 
 
In the event of unusual or life-threatening complications, treating investigators must 
immediately notify the Overall PI, 
  
 
5.5 
Duration of Follow Up 
 
Participants will have a follow up visit within 30 days of removal from protocol therapy 
(End of Treatment visit). Adverse event monitoring will continue through End of 
Treatment visit. Subjects who discontinue for reasons other than progressive disease will 
have post-treatment follow-up for disease status until disease progression, initiating a 
non-study cancer treatment, withdrawing consent or becoming lost to follow-up. Follow 
up scans are not required for patients who do not progress, but will be captured if 
possible. After documented disease progression each subject will be followed by 
telephone, chart review, or clinic visit for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. Regardless of reason for 
discontinuation, patients will be followed every 6 months until death or 2 years after 
treatment discontinuation. 
 
5.6 
Criteria for Taking a Participant Off Study  
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 


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27 
 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, 
must be documented in the case report form (CRF). 
 
An ODQ Treatment Ended/Off Study Form will be filled out when a participant comes 
off study. This form can be found on the ODQ website or obtained from the ODQ 
registration staff.  
 
5.7 
Clinical Criteria for Early Trial Termination 
Early trial termination may occur if the criteria specified below are met: 
 
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, including those determined by DSMC 
or study team from earlier safety monitoring in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
 
6. DOSING DELAYS  
 
Dose delays will be made as indicated in the following table(s). No dose 
lowering/modifications will occur; only dose holds. The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for dose delays. A copy of the CTCAE version 4.0 
can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
 
There will be no dose modifications for either pembrolizumab or Radium-223. Doses 
may be held for a maximum of 12 weeks for pembrolizumab and a maximum of 8 
weeks for Radium-223 for resolution of toxicity.  For delays longer than these intervals 
that are not due to toxicity of the agent and for which the patient was receiving clinical 
benefit, decisions to restart can be discussed with the PI and will be made on a case-by-
case basis. The patient may be continued on either agent if one is discontinued and the 
other is not thought to be contributing to the toxicity in question. 
 
Doses of either agent will not be omitted but can be given when the patient meets 
protocol specified criteria to treat. Interim reassessments between protocol specified 
dosing days are at the discretion of the treating physician.  


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28 
 
 
Scans will stay on the same every 12 week (+/- 7 days) schedule even if doses are 
delayed. 
 
6.1 
Dose Delay Guidelines for Pembrolizumab 
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology.  These adverse events may occur shortly after 
the first dose or several months after the last dose of treatment. Pembrolizumab must be 
withheld for drug-related toxicities and severe or life-threatening AEs as per the Table 
below. 
 
If an irAE is suspected, a thorough evaluation should be conducted in an effort to 
possibly rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior 
to diagnosing an irAE. Serological, immunological, and histological (biopsy) data 
should be considered to support the diagnosis of an immune-related toxicity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 5: Summary of Dosing Guidelines for Drug-Related Adverse Events (see more 
detailed recommendations for each event below the table) 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia 
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3 
Hold until toxicity resolves to Grade 0-1 
or permanently discontinue per treating 
investigator’s discretion 
Hold until toxicity resolves to Grade 0-1 or permanently discontinue 
per treating investigator’s discretion 
4 or 
Recurrent 
Grade 2 or 3 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while treatment for 
the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Myocarditis 
1-2 
Hold until toxicity resolves to Grade 0 
Per physician discretion, treat with corticosteroids. If 
pembrolizumab held and corticosteroid required, manage as per 
Grade 3. 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 or 
Recurrent 
Grade 2 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity1 
Intolerable/
Recurrent 
Grade 2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3 or Severe 
Toxicity resolves to Grade 0-1 
4  
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held and that do not recover to Grade 0-1 within 12 weeks of the last dose.   


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Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects should be placed back on pembrolizumab 
within 12 weeks of the last dose, unless otherwise discussed with the Overall PI and 
Merck contact. The reason for interruption should be documented in the patient's study 
record. 
 
The following are considered events that should be reported to the Sponsor-
Investigator within 24 hours of the site responsible investigator becoming aware of 
the event. The treatments are recommendations and the agents utilized should be 
determined by the treating clinician as deemed medically necessary. 
 
Pneumonitis  
The following AE terms, if considered ≥ Grade 2, should be reported to the Sponsor-
Investigator within 24 hours of the event: 
– Pneumonitis 
– Interstitial lung disease 
– Acute interstitial pneumonitis 
 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing 
and/or a cardiology consultation should be considered. All attempts should be made to 
rule out other causes such as metastatic disease, bacterial or viral infection. It is 
important that patients with a suspected diagnosis of pneumonitis be managed as 
per the guidance below until treatment-related pneumonitis is excluded. Treatment 
of both a potential infectious etiology and pneumonitis in parallel may be 
warranted. Management of the treatment of suspected pneumonitis with steroid 
treatment should not be delayed for a therapeutic trial of antibiotics. If an alternative 
diagnosis is established, the patient does not require management as below; however, the 
AE should be reported to the Sponsor-Investigator regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Report to Sponsor-Investigator 
– Hold pembrolizumab. 
– Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
– Consider ID consult 
– Conduct an in person evaluation approximately weekly 
– Consider frequent Chest X-ray as part of monitoring 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent. When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the 
patient develops a second episode of Grade 2 or higher pneumonitis. 


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Grade 3 and 4 events: 
– Report to Sponsor-Investigator 
– Discontinue pembrolizumab. 
– Hospitalize patient 
– Bronchoscopy with biopsy and/or BAL is recommended. 
– Immediately treat with intravenous steroids (e.g., methylprednisolone 125 mg IV). 
When symptoms improve to Grade 1 or less, a high dose oral steroid (e.g., prednisone 1 
to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) taper should be started 
and continued over no less than 4 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms 
within 48 to 72 hours, consider treatment with additional anti-inflammatory measures. 
Discontinue additional anti-inflammatory measures upon symptom relief and initiate a 
prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, 
initiate a re-tapering of steroids starting at a higher dose (e.g., prednisone 80 or 100 mg) 
followed by a more prolonged taper and administer additional anti-inflammatory 
measures, as needed 
– Prophylactic antibiotics against opportunistic infections are recommended. 
 
Diarrhea/Colitis  
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use 
of systemic steroids to treat the AE, should be reported to the Sponsor-Investigator within 
24 hours of the event: 
– Colitis 
– Colitis microscopic 
– Enterocolitis 
– Enterocolitis hemorrhagic 
– Gastrointestinal perforation 
– Intestinal obstruction 
– Necrotizing colitis 
– Diarrhea 
All attempts should be made to rule out other causes such as metastatic disease, bacterial 
or parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory 
bowel disease by examination for stool leukocytes, stool cultures, a Clostridium difficile 
titer and endoscopy. However, the AE should be reported to the Sponsor-Investigator 
regardless of etiology. 
 
Course of Action 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 
24 hours, abdominal pain, mucus or blood in stool): 
– Report to Sponsor-Investigator 
– Hold pembrolizumab. 
– Symptomatic Treatment 
– For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood 
and/or mucus, 
• Consider GI consultation and endoscopy to confirm or rule out colitis 


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32 
 
• Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
– When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– If symptoms worsen or persist > 3 days despite the above interventions, treat as Grade 3  
 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week): 
– Report to Sponsor-Investigator 
– Hold pembrolizumab. 
– Rule out bowel perforation. Imaging with plain films or CT can be useful. 
– Recommend consultation with Gastroenterologist and confirmation biopsy with 
endoscopy. 
– Treat with intravenous steroids (e.g., methylprednisolone 125 mg) followed by high 
dose oral steroids (e.g., prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg 
every 4 hours) When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Taper over 6 to 8 weeks in patients with 
diffuse and severe ulceration and/or bleeding. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms 
within 48 to 72 hours, consider treatment with additional anti-inflammatory measures 
(e.g., infliximab). 
-Discontinue additional anti-inflammatory measures upon symptom relief and initiate a 
prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, 
initiate a re-tapering of steroids starting at a higher dose of 80 or 100 mg followed by a 
more prolonged taper and administer additional anti-inflammatory measures as needed. 
 
Grade 4 events: 
– Report to Sponsor-Investigator 
– Permanently discontinue pembrolizumab. 
– Manage as per Grade 3. 
 
Endocrine 
The following AE terms, if considered ≥ Grade 3 or if ≥ Grade 2 and require 
holding/discontinuation/modification of pembrolizumab dosing, should be reported to the 
Sponsor-Investigator within 24 hours of the event: 
– Adrenal insufficiency 
– Hyperthyroidism 
– Hypophysitis 
– Hypopituitarism 
– Hypothyroidism 
– Thyroid disorder 
– Thyroiditis 
 


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33 
 
All attempts should be made to rule out other causes such as brain metastases, sepsis 
and/or infection. However, the AE should be reported to the Sponsor-Investigator 
regardless of etiology. 
 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or 
hyperthyroidism 
Grade 2-4 events: 
– Report to Sponsor-Investigator if appropriate 
– Hold pembrolizumab 
– Rule out infection and sepsis with appropriate cultures and imaging. 
– Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– Pituitary gland imaging should be considered (MRIs with gadolinium and selective cuts 
of the pituitary can show enlargement or heterogeneity and confirm the diagnosis). 
– Treat with prednisone 40 mg p.o. or equivalent per day. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) 
constitutes adrenal crisis. 
– Consultation with an endocrinologist may be considered. 
 
Hyperthyroidism and Hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
 
Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events: 
– Report to Sponsor-Investigator if appropriate (see Table 5) 
– Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. 
– Therapy with pembrolizumab can be continued while treatment for the thyroid disorder 
is instituted. 
– In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
– In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
– Consultation with an endocrinologist may be considered. 
 
Grade 3 hyperthyroidism events: 
– Report to Sponsor-Investigator 
– Hold pembrolizumab. 


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34 
 
– Rule out infection and sepsis with appropriate cultures and imaging. 
– Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed 
by oral prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 hyperthyroidism events: 
– Report to Sponsor-Investigator 
– Discontinue pembrolizumab. 
– Manage as per Grade 3 
 
Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia 
The following AE terms should be reported to the Sponsor-Investigator within 24 hours 
of the event: 
– Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA) 
– Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA). 
-Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt 
worsening of preexisting diabetes associated with laboratorial evidence of beta cell 
failure. All attempts should be made to rule out other causes such as type 2 diabetes 
mellitus (T2DM), T2DM decompensation, steroid-induced diabetes, physiologic stress-
induced diabetes, or poorly controlled pre-existing diabetes (either T1DM or T2DM), but 
events meeting the above criteria should be reported to the Sponsor-Investigator 
regardless of etiology. The patients may present with hyperglycemia (abrupt onset or 
abrupt decompensation) with clinical evidence of diabetic ketoacidosis or laboratory 
evidence of insulin deficiency, such as ketonuria, laboratory evidence of metabolic 
acidosis, or low or undetected c-peptide. 
 
Course of Action 
T1DM or Grade 3-4 Hyperglycemia events: 
- Report to Sponsor-Investigator if appropriate (see Table 5) 
- Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of beta cell failure, and resume pembrolizumab 
when patients are clinically and metabolically stable. 
- Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
- Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
- Consultation with an Endocrinologist is recommended. 
- Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and 
insulin may be obtained. 
 
Hepatic 


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35 
 
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose 
modification or use of systemic steroids to treat the AE), are considered Events of 
Clinical Interest (ECIs) and should be reported to the Sponsor-Investigator within 24 
hours of the event: 
– Autoimmune hepatitis 
– Hepatitis 
– Transaminase elevations 
All attempts should be made to rule out other causes such as metastatic disease, infection 
or other hepatic diseases. However, the AE should be reported regardless of etiology. See 
section 7.4 for ECI reporting details. 
 
Drug Induced Liver Injury (DILI) 
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the 
patient meets the laboratory criteria for potential DILI defined as: 
–  An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value 
that is greater than or equal to three times (3X) the institutional upper limit of normal 
(ULN) and 
– An elevated total bilirubin lab value that is greater than or equal to two times (2X) 
institutional ULN and 
– At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X 
institutional ULN, as a result of within-protocol-specific testing or unscheduled testing. 
 
Note that any hepatic immune ECI meeting DILI criteria should only be reported once as 
a DILI event. 
 
Course of Action 
Grade 2 events: 
– Report as ECI and to Sponsor-Investigator 
– Hold pembrolizumab when AST or ALT >3.0 to 5.0 times institutional ULN and/or 
total bilirubin >1.5 to 3.0 times institutional ULN. 
– Monitor liver function tests more frequently until returned to baseline values (consider 
weekly). 
–Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT 
returns to grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume pembrolizumab per protocol 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 events: 
– Report as ECI and to Sponsor-Investigator 
– Discontinue pembrolizumab when AST or ALT >5.0 times institutional ULN and/or 
total bilirubin >3.0 times institutional ULN. 
– Consider appropriate consultation and liver biopsy to establish etiology of hepatic 
injury, if necessary 
– Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When 
symptoms improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 


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36 
 
hours or prednisone at 1 to 2 mg/kg should be started and continued over no less than 4 
weeks. 
– If serum transaminase levels do not decrease 48 hours after initiation of systemic 
steroids, oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is 
not recommended due to its potential for hepatotoxicity. 
– Several courses of steroid tapering may be necessary as symptoms may worsen when 
the steroid dose is decreased. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Report as ECI and to Sponsor-Investigator 
– Permanently discontinue pembrolizumab 
– Manage patient as per Grade 3 above 
 
Neurologic 
The following AE terms, regardless of grade, should be reported to the Sponsor-
Investigator within 24 hours of the event: 
– Autoimmune neuropathy 
– Demyelinating polyneuropathy 
– Guillain-Barre syndrome 
– Myasthenic syndrome 
– Encephalitis 
 
All attempts should be made to rule out other causes such as metastatic disease, other 
medications or infectious causes. However, the AE should be reported to the Sponsor-
Investigator regardless of etiology 
 
Course of Action 
Grade 2 events: 
– Report to Sponsor-Investigator 
– Moderate (Grade 2) – consider withholding pembrolizumab. 
– Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
– Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 and 4 events: 
– Report to Sponsor-Investigator 
– Discontinue pembrolizumab 
– Obtain neurology consultation. Consider biopsy for confirmation of diagnosis 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. If condition worsens, consider IVIG or other immunosuppressive therapies 
as per local guidelines. When symptoms improve to Grade 1 or less, steroid taper should 
be started and continued over no less than 4 weeks. 
 


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37 
 
Hematologic 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of 
systemic steroids to treat the AE, should be reported to the Sponsor-Investigator within 
24 hours of the event: 
– Autoimmune hemolytic anemia 
– Aplastic anemia 
– Disseminated Intravascular Coagulation (DIC) 
– Haemolytic Uraemic Syndrome (HUS) 
– Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
– Thrombotic Thrombocytopenic Purpura (TTP) 
– Any Grade 4 anemia regardless of underlying mechanism 
 
All attempts should be made to rule out other causes such as metastases, sepsis and/or 
infection.  
Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, 
haptoglobin, bone marrow biopsy or Coomb’s test, etc., should be considered to confirm 
the diagnosis. However, the AE should be reported to the Sponsor-Investigator regardless 
of etiology. 
 
Course of Action 
Grade 2 events: 
– Report to Sponsor-Investigator if proven to have autoimmune etiology 
– Okay to continue pembrolizumab if no autoimmune signs or pending workup 
– If signs of autoimmune effects consider hematology consultation and prednisone 1-2 
mg/kg daily  
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 events: 
– Report to Sponsor-Investigator if proven to have autoimmune etiology 
– Hematology consultation to rule out autoimmune etiology 
– Hold pembrolizumab.  Discontinuation should be considered as per specific protocol 
guidance. 
– Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) 
as appropriate 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Report to Sponsor-Investigator 
– Hematology consultation 
– Discontinue pembrolizumab for all solid tumor indications 
– Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) 
as appropriate 
 
Ocular 


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38 
 
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of 
systemic steroids to treat the AE, should be reported to the Sponsor-Investigator within 
24 hours of the event: 
– Uveitis 
– Iritis 
All attempts should be made to rule out other causes such as metastatic disease, infection 
or other ocular disease (e.g. glaucoma or cataracts). However, the AE should be reported 
to the Sponsor-Investigator regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Evaluation by an ophthalmologist is strongly recommended. 
– Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics. 
– Discontinue pembrolizumab as per protocol if symptoms persist despite treatment with 
topical immunosuppressive therapy. 
 
Grade 3 events: 
– Evaluation by an ophthalmologist is strongly recommended 
– Hold pembrolizumab and consider permanent discontinuation as per specific protocol 
guidance. 
– Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per 
day. When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Evaluation by an ophthalmologist is strongly recommended 
– Permanently discontinue pembrolizumab. 
– Treat with corticosteroids as per Grade 3 above 
 
Renal 
The following AEs if ≥ Grade 2 should be reported to the Sponsor-Investigator within 24 
hours of the event: 
– Nephritis 
– Nephritis autoimmune 
– Renal failure 
– Renal failure acute 
 
Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic 
steroids to treat the AE. 
All attempts should be made to rule out other causes such as obstructive uropathy, 
progression of disease, or injury due to other chemotherapy agents. A renal consultation 
is recommended. However, the AE should be reported to the Sponsor-Investigator 
regardless of etiology. 


DF/HCC Protocol #: 16-498 
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39 
 
 
Course of Action 
Grade 2 events: 
– Hold pembrolizumab 
– Treatment with prednisone 1-2 mg/kg p.o. daily. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3-4 events: 
– Discontinue pembrolizumab 
– Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or 
equivalent once per day. 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
Skin 
Rash and Pruritus 
The following AEs if ≥ Grade 3 should be reported to the Sponsor-Investigator within 24 
hours of the event: 
– Pruritus 
– Rash 
– Rash generalized 
– Rash maculo-papular 
– In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in 
the physician's judgment, should be treated as an ECI. Clinical significance is left to the 
physician to determine, and could possibly include rashes such as the following: 
o rash with a duration >2 weeks; OR 
o rash that is >10% body surface area; OR 
o rash that causes significant discomfort not relieved by topical medication or 
temporary cessation of study drug. 
 
Other Skin events 
The following AEs, regardless of grade, should be reported to the Sponsor-Investigator 
within 24 hours of the event: 
– Dermatitis exfoliative 
– Erythema multiforme 
– Stevens-Johnson syndrome 
– Toxic epidermal necrolysis 
Please note, the AE should be reported to the Sponsor-Investigator regardless of etiology. 
 
 
 
 
 


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Course of Action 
Grade 2 events: 
– Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in 
combination with oral anti-pruritics (e.g., diphenhydramine HCl or hydroxyzine HCl). 
– Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
 
Grade 3 events: 
– Hold pembrolizumab. 
– Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
– Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or 
equivalent once per day or dexamethasone 4 mg four times orally daily. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Permanently discontinue pembrolizumab. 
– Dermatology consultation and consideration of biopsy and clinical dermatology 
photograph. 
– Initiate steroids at 1 to 2 mg/kg prednisone or equivalent. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
 
Immediate Evaluation for Potential Skin events (Recommended but not required) 
 
A. Photographs: 
Every attempt should be made to get a photograph of the actual skin lesion or rash as 
soon as possible. 
Obtain appropriate consent for subject photographs and document in the patient 
notes. 
– Take digital photographs of: 
• the head (to assess mucosal or eye involvement), 
• the trunk and extremities, and 
• a close-up of the skin lesion/rash. 
– If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed 
marker of distance. 
– The time/date stamp should be set in the 'ON' position for documentation purposes. 
– Photographs should be stored with the subject’s study records. 
– The Sponsor-Investigator may request copies of photographs. The local study contact 
(e.g., CRA) will provide guidance to the site, if needed. 
 
B. Past Medical History: 
Collect past medical history relevant to the event. Any preexisting conditions not 
previously reported (e.g., drug allergy) should be entered into the Medical History eCRF. 
 


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C. Presentation of the Event: 
Collect information on clinical presentation and potential contributing factors. This 
information should be summarized and entered in narrative format in the AE eCRF. 
Please use the available free-text fields, such as Signs and Symptoms. Note pertinent 
negatives where applicable to reflect that the information was collected. Any treatments 
administered should be entered on the Concomitant Medication eCRF. 
 
D. Vitals Signs and Standard Laboratory Tests: 
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record 
on the Vital Signs eCRF. Perform standard laboratory tests (CBC with manual 
differential and serum chemistry panel, including LFTs). 
 
E. Focused Skin Examination: 
Perform a focused skin examination. Information should be summarized and entered on 
the Adverse Experience eCRF as part of the narrative. 
 
F. Dermatology Consult 
Refer the subject to a dermatologist as soon as possible. 
– For a “severe rash”, the subject must be seen within 1-2 days of reporting the event. 
– For clinically significant rash, the subject should be seen within 3-5 days. 
The dermatologist should submit a biopsy sample to a certified dermatopathology 
laboratory or to a pathologist experienced in reviewing skin specimens. The site should 
provide the dermatologist with all relevant case history, including copies of clinical 
photographs and laboratory test results. 
 
Other/Miscellaneous Immune Related Toxicities 
The following AEs, regardless of grade, should be reported to the Sponsor-Investigator 
within 24 hours of the event: 
– Myocarditis 
– Pericarditis 
– Pancreatitis 
– Any additional Grade 3 or higher event, which the physician considers to be immune 
related 
All attempts should be made to rule out other causes. Therapeutic specialists should be 
consulted as appropriate. However, the AE should be reported to the Sponsor-
Investigator regardless of etiology. 
 
Course of Action 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
– Withhold pembrolizumab. 
– Systemic corticosteroids may be indicated. 
– Consider biopsy for confirmation of diagnosis. 
– If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
 
Grade 3 events: 
– Hold pembrolizumab 


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– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
– When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
– Permanently discontinue if any grade 3 or higher cardiac toxicity including myocarditis 
and pericarditis even if improves/resolves 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment 
may be restarted as specified in the protocol 
 
Grade 4 events: 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
– Discontinue pembrolizumab 
 
Infusion Reactions 
The following AE terms, regardless of grade, should be reported to the Sponsor-
Investigator within 24 hours of the event: 
– Allergic reaction 
– Anaphylaxis 
– Cytokine release syndrome 
– Serum sickness 
– Infusion reactions 
– Infusion-like reactions 
 
Please note, the AE should be reported to the Sponsor-Investigator regardless of etiology. 
 
Course of Action 
Refer to infusion reaction table below. 
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. Table below shows treatment guidelines for subjects who 
experience an infusion reaction associated with administration of pembrolizumab. 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6: Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
 
Subjects who re-develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
 
 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
 
 
 
 
 
 
 
 


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Table 7: General Approach to Handling irAEs not otherwise specified 
 
irECI 
Withhold/Discontinue 
pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold pembrolizumab 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold 
pembrolizumab 
Discontinue at investigator 
discretion for safety/tolerability 
or if unable to reduce 
corticosteroid dose to < 
10 mg per day prednisone 
equivalent within 12 weeks of 
toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 
4 weeks. 
 
All AEs are to be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0 
(http://ctep.cancer.gov). 
 
If an irAE does not resolve or improve to ≤ Grade 1 within 12 weeks after last 
administration of pembrolizumab, study therapy discontinuation should be 
considered after discussion with the PI. 
 
Table 8: Dose Modifications and Management of Nausea/Vomiting Thought Related 
to Pembrolizumab* 
Nausea/Vomiting 
Management 
Next Dose  
≤ Grade 1 
Supportive care 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  
Hold until ≤ Grade 1.  Resume at 
same dose level.** 
Grade 3 
Hold until < Grade 2.  
Hold until < Grade 2.  Resume at 
same dose level.** 
Grade 4 
Off protocol therapy 
Off protocol therapy if attributed to 
study drugs 
*If nausea/vomiting thought unrelated, dosing of study drugs is per investigator discretion 
**Participants requiring a delay of >12 weeks should go off pembrolizumab if nausea/ 
vomiting thought related to pembrolizumab. 
Recommended management for all grades: antiemetics. 
 
 
 
 
 
 
 
 


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6.2 
Dose Modifications for Radium-223 
 
Every effort should be made to administer the full dosing regimen of radium-223. 
Adjustment of dose level is not permitted. Study visits during the treatment period 
should occur at 4 week intervals (within a window of +/- 7 days). Dosing delays may be 
instituted under the following circumstances: 
 
Myelosuppression:   
Treatment-related changes in hematology parameters may occur.  
 
• If a patient experiences CTCAE version 4.0 grade 3 or 4 neutropenia, 
thrombocytopenia, or anemia the administration of study drug should be delayed 
until recovery to grade 2 or better.  
• If a patient experiences CTCAE version 4.0 grade 3 or 4 neutropenia, 
thrombocytopenia, or anemia lasting 8 weeks, further Radium-223 
administrations must be discontinued.  
• Blood transfusion is acceptable between Radium-223 administrations.  
 
Spinal Cord Compression: 
If the patient experiences spinal cord compression during the treatment period, the patient 
should be treated for the event, and may receive further study drug administration if 
adequately recovered.  
 
Surgical Intervention: 
If surgery is required, the patient should continue with study treatment, if this is 
considered safe in the treating investigator’s opinion. The surgeon needs to be notified 
that the patient has been given radioactive drug, and needs to follow the guidelines for 
radioactive protection.   
 
Non-pathological fractures: 
For traumatic fractures in weight-bearing bones during treatment phase, Radium-223 
administration should be delayed for at least 2-4 weeks from the time of fracture.  
 
Pathological fractures: 
Pathological fractures may occur as the result of either progressive disease or increased 
physical activity associated with significant pain palliation. Pathologic fractures are to be 
treated in a manner that attempts to maintain the best functional status and quality of life. 
Study treatment may continue as planned. 
 
Other Radium-223 related toxicities:  
• If a patient experiences CTCAE version 4.0 grade 3 or 4 toxicity related to 
radium-223, the administration of radium-223 should be delayed until recovery to 
grade 2 or better.  
• If a patient experiences CTCAE version 4.0 grade 3 or 4 toxicity related to 
radium-223 lasting 8 weeks, further study drug administrations must be 
discontinued.  


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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting 
in addition to routine reporting. 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product or protocol-specified procedure, whether or not considered related to 
the medicinal product or protocol-specified procedure.  Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition that is temporally associated with the use of the Merck’s product, is also an 
adverse event. 
 
Adverse events may occur during the course of the use of Merck product in clinical trials 
or within the follow-up period specified by the protocol, or prescribed in clinical practice, 
from overdose (whether accidental or intentional), from abuse and from withdrawal. 
 
Adverse events may also occur in screened subjects during any pre-allocation baseline 
period as a result of a protocol-specified intervention, including washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
 
All adverse events will be recorded from the time the consent form is signed through 30 
days following cessation of treatment and at each examination on the Adverse Event case 
report forms/worksheets.  
 
7.1 
 Expected Toxicities 
 
7.1.1 Adverse Events 
 
7.1.1.1 
Adverse Event Expected with Pembrolizumab (MK-3475, Keytruda) 4 
 
Clinical Trial Experience (selected portions of US Prescribing Information using the 
melanoma population as the disease with the greatest clinical experience). 
 
Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in the clinical trials of a drug cannot be directly compared to rates in the 
clinical trials of another drug and may not reflect the rates observed in practice. 


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The data described in the WARNINGS and PRECAUTIONS section and below reflect 
exposure to KEYTRUDA in an uncontrolled, open-label, multiple cohort trial (Trial 1). 
In Trial 1, the safety data are available from 411 patients with unresectable or metastatic 
melanoma and 550 patients with metastatic NSCLC who received KEYTRUDA at either 
2 mg/kg every 3 weeks (n=61) or 10 mg/kg every 2 or 3 weeks (n=489). 
 
Among the 411 patients with metastatic melanoma enrolled in Trial 1, the median 
duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 24.6 months) with 
a median of 10 doses (range 1 to 51). The study population characteristics were: median 
age of 61 years (range 18 to 94), 39% age 65 years or older, 60% male, 97% white, 73% 
with M1c disease, 8% with brain metastases, 35% with elevated LDH, 54% with prior 
exposure to ipilimumab, and 47% with two or more prior systemic therapies for advanced 
or metastatic disease. 
 
KEYTRUDA was discontinued for adverse reactions in 9% of the 411 patients. Adverse 
reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA 
were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of 
patients receiving KEYTRUDA. The most frequent serious adverse drug reactions 
reported in 2% or more of patients in Trial 1 were renal failure, dyspnea, pneumonia, and 
cellulitis. 
 
Table 9 presents adverse reactions identified from analyses of 89 patients with 
unresectable or metastatic melanoma who received KEYTRUDA 2 mg/kg every three 
weeks in one cohort of Trial 1. Patients had documented disease progression following 
treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This 
cohort of Trial 1 excluded patients with severe immune-related toxicity related to 
ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or 
Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or 
equivalent dose) for greater than 12 weeks; a medical condition that required systemic 
corticosteroids or other immunosuppressive medication; a history of pneumonitis or 
interstitial lung disease; or any active infection requiring therapy, including HIV or 
hepatitis B or C. Of the 89 patients in this cohort, the median age was 59 years (range 18 
to 88), 33% were age 65 years or older, 53% were male, 98% were white, 44% had an 
elevated LDH, 84% had Stage M1c disease, 8% had brain metastases, and 70% receive 
two or more prior therapies for advanced or metastatic disease. The median duration of 
exposure to KEYTRUDA was 6.2 months (range 1 day to 15.3 months) with a median of 
nine doses (range 1 to 23). Fifty-one percent of patients were exposed to KEYTRUDA 
for greater than 6 months and 21% for greater than 1 year. 
 
KEYTRUDA was discontinued for adverse reactions in 6% of the 89 patients. The most 
common adverse reactions (reported in at least 20% of patients) were fatigue, cough, 
nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. 
 
 
 


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Table 9: Adverse Reactions in ≥10% of Patients with Unresectable or Metastatic 
Melanoma 
 
 
Other clinically important adverse reactions observed in up to 10% of patients treated 
with KEYTRUDA were: 
Infections and infestations:  sepsis 
 
 
 


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Table 10: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients 
with Unresectable or Metastatic Melanoma 
 
 
Immune-Related Adverse Events 
 
An irAE is defined as a clinically significant AE of any organ that is associated 
with study drug exposure, is of unknown etiology, and is consistent with an immune-
related mechanism. The most commonly reported immune-related adverse events 
across the dose-schedules in patients with melanoma were rash, pruritus, vitiligo, 
hypothyroidism, arthralgia, diarrhea, and pneumonitis. All occurred in less than 5% of 
patients.  The organ most frequently affected by irAEs with pembrolizumab is the 
skin.   Less frequently affected tissues include thyroid gland, colon, lung, kidney, and 
liver.  
 
These events can occur after the first dose to several months after the last dose of 
treatment. Mild irAEs are usually treated symptomatically and do not require dosing 
delays or discontinuation. Higher grade and persistent lower grade irAEs typically 
necessitate withholding or discontinuing treatment and administration of systemic 
steroids or other immunosuppressive agents (such as tumor necrosis factor blockers), 
when systemic steroids are not effective. Early recognition of irAEs and initiation of 
treatment are critical to reduce the risk of complications, since the majority of irAEs are 
reversible with the use of steroids and other immune suppressants. 
 
Immune-mediated adverse reactions 
• Pneumonitis 
• Colitis 
• Hepatitis 
• Nephritis and renal dysfunction 
• Endocrinopathies: 
o Hypophysitis 
o Type 1 diabetes mellitus including diabetic ketoacidosis 
o Thyroid disorders: hyperthyroidism, hypothyroidism 


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• Pancreatitis 
• Guillain-Barre Syndrome 
• Myositis 
• Arthritis 
• Uveitis (<1%) 
• Severe skin reactions: exfoliative dermatitis (<1%) 
• Infusion reactions (severe: <0.1%) 
• Hemolytic anemia 
• Vasculitis 
• Partial seizures related to inflammatory foci in brain parenchyma 
• Serum sickness 
• Myasthenia gravis 
 
Select potential immune-mediated adverse reactions 
 
Table below presents select treatment-related, potential immune-mediated adverse 
reactions that occurred in patients receiving KEYTRUDA. In addition, across 
clinical studies with KEYTRUDA in approximately 5000 patients, induction of type 1 
diabetes mellitus has been reported in 0.1% of patients. 
 
Table 11: Select Treatment-related, Potential Immune-mediated Adverse Reactions 
 
7.1.1.2 
Adverse Events Expected with Radium-2233  
 
Bone Marrow Suppression  
In the randomized phase 3 trial, 2% of patients on the radium-223 arm experienced bone 
marrow failure or ongoing pancytopenia compared to no patients treated with placebo. 
There were two deaths due to bone marrow failure and for 7 of 13 patients treated with 
radium-223, bone marrow failure was ongoing at the time of death. Among the 13 
patients who experienced bone marrow failure, 54% required blood transfusions. Four 
percent (4%) of patients on the radium-223 arm and 2% on the placebo arm permanently 
discontinued therapy due to bone marrow suppression. 
 


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In the randomized trial, deaths related to vascular hemorrhage in association with 
myelosuppression were observed in 1% of radium-223-treated patients compared to 
0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), 
serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated 
with radium-223 and placebo. Myelosuppression; notably thrombocytopenia, 
neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with 
radium-223. In the randomized trial, complete blood counts (CBCs) were obtained 
every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not 
well characterized. In a separate single-dose phase 1 study of radium-223, neutrophil 
and platelet count nadirs occurred 2 to 3 weeks after radium-223 administration at doses 
that were up to 1 to 5 times the recommended dose, and most patients recovered 
approximately 6 to 8 weeks after administration. 
 
Clinical Trials Experience 
 
In the randomized clinical trial in patients with metastatic castration-resistant prostate 
cancer with bone metastases, 600 patients received intravenous injections of 50 kBq/kg 
(1.35 microcurie/kg) of radium-223 and best standard of care and 301 patients received 
placebo and best standard of care once every 4 weeks for up to 6 injections.2  Prior to 
randomization, 58% and 57% of patients had received docetaxel in the radium-223 and 
placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) 
for radium-223 and 18 weeks (5 cycles) for placebo. 
 
The most common adverse reactions (≥ 10%) in patients receiving radium-223 were 
nausea, diarrhea, vomiting, and peripheral edema. Grade 3 and 4 adverse events were 
reported among 57% of radium-223-treated patients and 63% of placebo-treated patients. 
The most common hematologic laboratory abnormalities in radium-223-treated 
patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, 
and neutropenia. 
 
Treatment discontinuations due to adverse events occurred in 17% of patients who 
received radium-223 and 21% of patients who received placebo. The most common 
hematologic laboratory abnormalities leading to discontinuation for radium-223 were 
anemia (2%) and thrombocytopenia (2%). 
 
The Table below shows adverse reactions occurring in ≥ 2% of patients and for which the 
incidence for radium-223 exceeds the incidence for placebo. 
 
 
 
 
 
 
 
 
 


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Table 12: Adverse Reactions in the Randomized Trial of Radium and best standard 
of care vs. placebo and best standard of care 
 
 
Laboratory Abnormalities 
The Table below shows the hematologic laboratory abnormalities occurring in > 10% of 
patients and for which the incidence for radium-223 exceeds the incidence for placebo. 
 
Table 13: Hematologic Laboratory Abnormalities 
 
 
As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on 
radium-223 and in 2% of patients on placebo. Among patients who received radium-
223, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of 
docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 
3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who 
have received prior docetaxel. 
 
Fluid Status 
Dehydration occurred in 3% of patients on radium-223 and 1% of patients on placebo. 
Radium-223 increases adverse reactions such as diarrhea, nausea, and vomiting which 
may result in dehydration. 
 
Injection Site Reactions 
 
Erythema, pain, and edema at the injection site were reported in 1% of patients on 
radium-223. 
 


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Secondary Malignant Neoplasms 
 
Radium-223 contributes to a patient’s overall long-term cumulative radiation exposure. 
Long-term cumulative radiation exposure may be associated with an increased risk of 
cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, 
including osteosarcomas, in rats following administration of radium-223 dichloride, 
radium-223 may increase the risk of osteosarcoma or other secondary malignant 
neoplasms. However, the overall incidence of new malignancies in the randomized trial 
was lower on the radium-223 arm compared to placebo (<1% vs. 2%; respectively), but 
the expected latency period for the development of secondary malignancies exceeds the 
duration of follow up for patients on the trial. 
 
7.2 
 Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the 
adverse event varies in nature, intensity or frequency from the expected 
toxicity information. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting  
 
A serious adverse event is any adverse event occurring at any dose or during any use of 
the study drugs that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event in the opinion of the treating physician or PI 


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• All bone fractures need to be reported as either AE(s) or SAEs if the criteria of SAE 
were met, regardless of the investigator’s causality assessment for a minimum of 1 
year after the last dose of radium-223. Taking into consideration applicable 
guidelines, bone health agents (BHA) such as bisphosphonates or denosumab are 
recommended. 
 
From the time of consent up to study drug initiation, only serious adverse events deemed 
related to study procedures are required to be reported to the Overall PI. Investigators 
must report to the Overall PI any serious adverse event (SAE) that occurs after the initial 
dose of study treatment, during treatment, or within 90 days of the last dose of treatment 
on the local institutional SAE form.   
 
Any serious adverse event, or follow up to a serious adverse event, deemed related to study 
procedures from the time of consent up to study drug initiation, must be reported within 24 
hours to the Sponsor (DFCI) and within 2 working days to Merck Global Safety.  Any 
serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study, that occurs to any subject from the 
time of study drug initiation through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck 
product, must be reported within 24 hours to the Sponsor (DFCI) and within 2 working 
days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator 
at any time outside of the time period specified in the previous paragraph also must be 
reported immediately to the Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  215-993-1220 
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; 
 at the time of submission 
to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
 
For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical event equivalent to an 
unexpected grade 2 or 3 with a possible, probable or definite attribution, all grade 4 


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toxicities (except those that are expected AND listed as not reportable in this protocol), 
and grade 5 (death) regardless of study phase or attribution. 
 
7.3.1 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the 
DFCI Office for Human Research Studies (OHRS) per the DFCI IRB reporting 
policy.  
 
7.4 
Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; 
 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant 
must be reported within 2 working days to Merck Global Safety if it causes the 
participant to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
participant initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to 
an ECI, whether or not related to Merck product, must be reported within 2 working days 
to Merck Global Safety. 
Events of clinical interest for this trial include: 
 
1.  an overdose of Merck product, as defined in Section 7.7.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor and to Merck, that is not 
associated with clinical symptoms or abnormal laboratory results.  
 
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  
 
 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the 


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FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any 
serious adverse event that meets the FDA’s criteria for expedited reporting following the 
reporting requirements and timelines set by the FDA. 
 
7.6 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any 
participant safety reports or sentinel events that require reporting according to 
institutional policy.  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI 
on the toxicity case report forms.  AEs reported through expedited processes (e.g., 
reported to the IRB, FDA, etc.) must also be reported in routine study data 
submissions. 
 
7.7.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available 
on the treatment of overdose of pembrolizumab. Appropriate supportive treatment should 
be provided if clinically indicated. In the event of overdose, the subject should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck 
product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported 
as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 
hours to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; 
 
 
7.7.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation in a 
male subject's female partner that occurs during the trial or within 120 days of 
completing the trial completing the trial, or 30 days following cessation of treatment if 


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the subject initiates new anticancer therapy, whichever is earlier.  All female partners of 
male subjects who become pregnant must be followed to the completion/termination of 
the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor and within 2 working days 
to Merck Global Safety. (Attn: Worldwide Product Safety; 
 
 
 
8. PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational or other 
agents administered in this study can be found in Section 7.1. 
 
8.1 
Pembrolizumab4 
 
8.1.1 Description 
 
Pembrolizumab (MK-3475) is a humanized anti-PD-1 mAb of the IgG4/kappa 
isotype with a stabilizing S228P sequence alteration in the fragment crystallizable (Fc) 
region.  Pembrolizumab binds to human PD-1 and blocks the interaction between PD-
1 and its ligands.   
 
The theoretical molecular weight of the polypeptide is 146,288 Da and its 
theoretical pI is 7.5. The parental murine anti-human PD-1 antibody (hPD-1.09A) 
was produced by immunizing mice with hPD-1 DNA.  The pembrolizumab antibody 
was generated by humanization of the parental antibody by the Medical Research 
Council (Cambridge, UK) using complementarily-determining region (CDR) grafting 
technology (U.S.  Patent No. 5,225,539). The gene segments encoding the variable 
heavy and light chains of pembrolizumab, as well as human IgG4, were codon-
optimized, synthesized, and ligated into a vector. 
 
A single expression plasmid, pAPD11V1-GA was constructed for the expression of 
both the heavy and light antibody chains of pembrolizumab.  The nucleotide sequences 
encoding the heavy and light chains, along with their respective promoters and poly A 
signal sequences have been confirmed by DNA sequence analysis.  The pAPD11V1-GA 
expression vector was subsequently used to transfect CHO-DXB-11 cells for the 
development of the pembrolizumab-producing cell line. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (see IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement 
is durable (>21 days).  
 
 
 


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8.1.2 Form 
 
Table 14: Form of pembrolizumab 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
Two drug product (DP) dosage forms are available for pembrolizumab: a white to 
off-white lyophilized powder, 50 mg/vial, and a liquid, drug product 100 mg/vial, 
both in Type I glass vials intended for single use only.  The pembrolizumab Solution 
for Infusion 100 mg/vial will be used in this study. It is a liquid drug product 
(manufactured using the fully formulated DS), and has the identical formulation as that 
of the reconstituted lyophilized vial. 
 
8.1.3 Storage and Stability 
 
Drug should be stored under refrigerated conditions (2°C - 8°C). 
 
8.1.4 Handling 
 
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. 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment.  
 
8.1.5 Availability 
 
Merck will provide the investigational supply of pembrolizumab to the study site 
pharmacies at no charge to the site or patient. 
 
8.1.6 Preparation 
 
The product after reconstitution with sterile water for injection and the liquid 
drugproduct are a clear to opalescent solution which may contain proteinaceous and 
extraneous particulates.  The reconstituted lyophilized product and the liquid product 
are extraneous particulates.  The reconstituted lyophilized product and the liquid 
product are intended for IV administration. The reconstituted DP solution or the 
liquid DP can be further diluted with normal saline in IV containers made of polyvinyl 
chloride (PVC) or non-PVC material. Reconstituted vials should be immediately used to 
prepare the infusion solution in the IV bag and the infusion solution should be 
immediately administered.  If not used immediately, vials and/or IV bags may be stored 


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at 2-8 °C for up to a cumulative time of 20 hours.  If refrigerated, the vials and/or IV 
bags should be allowed to equilibrate to room temperature prior to subsequent use.  
Pembrolizumab solutions may be stored at room temperature for a cumulative time of 
up to 6 hours.  This includes room temperature storage of reconstituted or liquid DP 
solution in vials, room temperature storage of infusion solution in the IV bag and the 
duration of infusion.  See Pharmacy Manual for additional information on dose 
preparation and administration. 
 
8.1.7 Administration 
 
Pembrolizumab will be given by intravenous infusion over 30 minutes (-5min, +10 min) 
 
See Pharmacy Manual for additional information on dose preparation and administration. 
 
8.1.8 Ordering 
 
The study site will order the product from Merck. 
 
8.1.9 Accountability 
 
The investigator, or a responsible party designated by the investigator, will maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.10 Destruction and Return 
 
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. 
 
8.2 
Radium-2233 (Xofigo) 
 
8.2.1 Description  
 
The alpha-pharmaceutical radium-223 is a ready-to-use, sterile, non-pyrogenic, clear and 
colorless aqueous solution of radium-223 dichloride (223RaCl2) for IV administration. It 
should not be diluted or mixed with any solutions. Each vial for a single use only. 
 
Radium-223 is an alpha particle emitter with a physical half-life of 11.4 days. The 
product is isotonic and has a pH of 6.0-8.0. The radioactive concentration at the reference 
date is 1000 kBq/mL. The product has a pre-calibration of 14 days. When administered 


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on a day other than the reference day, the volume should be corrected according to the 
physical decay table. 
 
8.2.2 Form 
 
The volume per vial is 6 mL, corresponding to 6 MBq at the calibration day.  
 
All study drugs will be labeled according to the requirements of local law and legislation. 
For all study drugs, a system of numbering in accordance with all requirements of GMP 
will be used, ensuring that each dose of study drug can be traced back to the respective 
bulkware of the ingredients.  
 
8.2.3 Storage and Stability 
 
Radium-223 has a shelf life of 28 days from production day, when stored at ambient 
temperature. The shelf life has been demonstrated for temperatures from cold storage (2-
8°C) up to 40°C. In addition, it has been shown that the product quality is not jeopardized 
upon freezing. 
 
Do not store above 40°C (104°F). If the syringes have been stored in a refrigerator, they 
should be left at room temperature for 1 hour prior to use, since cold material should not 
be injected in a patient. Store radium-223 in the original container or equivalent radiation 
shielding. This preparation is approved for use by persons under license by the Nuclear 
Regulatory Commission or the relevant regulatory authority of an Agreement State. 
 
8.2.4 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment.  
 
General warning 
Radium-223 (an alpha particle-emitting pharmaceutical) should be received, used and 
administered only by authorized persons in designated clinical settings. The receipt, 
storage, use, transfer and disposal radium-223 are subject to the regulations and/or 
appropriate licenses of the competent official organization. 
 
Radium-223 should be handled by the user in a manner, which satisfies both radiation 
safety and pharmaceutical quality requirements. Appropriate aseptic precautions should 
be taken.  
 
Radiation protection 
 
The administration of radium-223 is associated with potential risks to other persons 
(e.g., medical staff, caregivers and patient’s household members) from radiation or 
contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, 


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radiation protection precautions must be taken in accordance with national and local 
regulations. 
 
For drug handling 
 
Follow the normal working procedures for the handling of radiopharmaceuticals and 
use universal precautions for handling and administration such as gloves and barrier 
gowns when handling blood and bodily fluids to avoid contamination. In case of contact 
with skin or eyes, the affected area should be flushed immediately with water. In the 
event of spillage of radium-223, the local radiation safety officer should be contacted 
immediately to initiate the necessary measurements and required procedures to 
decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine­ 
tetraacetic acid (EDTA) solution is recommended to remove contamination. 
 
For patient care 
 
Whenever possible, patients should use a toilet and the toilet should be flushed several 
times after each use. When handling bodily fluids, simply wearing gloves and hand 
washing will protect caregivers. Clothing soiled with radium-223 or patient fecal 
matter or urine should be washed promptly and separately from other clothing. 
 
Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as 
alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as 
gamma-radiation is 1.1%. The external radiation exposure associated with handling of 
patient doses is expected to be low, because the typical treatment activity will be below 
8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable 
(ALARA) principle for minimization of radiation exposure, it is recommended to 
minimize the time spent in radiation areas, to maximize the distance to radiation sources, 
and to use adequate shielding. Any unused product or materials used in connection with 
the preparation or administration are to be treated as radioactive waste and should be 
disposed of in accordance with local regulations. 
 
The gamma radiation associated with the decay of radium-223 and its daughters allows 
for the radioactivity measurement of radium-223 and the detection of contamination with 
standard instruments. 
 
8.2.5 Availability 
 
Radium-223 is commercially available. 
 
Xofigo (radium Ra 223 dichloride injection) is available in single-use vials containing 6 
mL of solution at a concentration of 1,000 kBq/mL (27 microcurie/mL) at the reference 
date with a total radioactivity of 6,000 kBq/vial (162 microcurie/vial) at the reference 
date. 
 


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8.2.6 Preparation 
 
Personnel should use appropriate protective clothing and equipment during syringe 
handling to prevent contamination with the radioactive solution (medical gloves / 
protective glasses).  
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
 
Radium-223 is a ready-to-use solution and should not be diluted or mixed with any 
solutions. Each vial is for single use only. 
 
The dose will be delivered in a ready-to-use prefilled syringe with a certified activity. 
The activity in the syringe will be assayed in the dose calibrator according to standard 
institutional practice and guidelines for administration of therapeutic 
radiopharmaceuticals to patients.   
 
8.2.7 Administration 
 
Administer radium-223 by slow intravenous injection over 1 minute (or longer depending 
on local institutional standards). 
Flush the intravenous access line or cannula with isotonic saline before and after injection 
of radium-223. 
 
Before administration of radium-223, the participant must be well hydrated; the 
participant should be instructed to drink ad libitum. Aseptic technique should be used in 
the administration of radium-223. The study medication will be administered as a bolus 
IV injection (up to 1 minute or longer depending on local institutional standards). After 
administration, the equipment used in connection with the preparation and administration 
of drug is to be treated as radioactive waste and should be disposed in accordance with 
local procedure for the handling of radioactive material.  
 
8.2.8 Dosimetry  
 
The absorbed radiation doses in major organs were calculated based on clinical 
biodistribution data in five patients with castration-resistant prostate cancer. Calculations 
of absorbed radiation doses were performed using OLINDA/EXM (Organ Level INternal 
Dose Assessment/EXponential Modeling), a software program based on the Medical 
Internal Radiation Dose (MIRD) algorithm, which is widely used for established beta and 
gamma emitting radionuclides. For radium-223, which is primarily an alpha particle-
emitter, assumptions were made for intestine, red marrow and bone/osteogenic cells to 
provide the best possible absorbed radiation dose calculations for radium-223, 
considering its observed biodistribution and specific characteristics. 
 
The calculated absorbed radiation doses to different organs are listed in the PI. The 
organs with highest absorbed radiation doses were bone (osteogenic cells), red marrow, 


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upper large intestine wall, and lower large intestine wall. The calculated absorbed doses 
to other organs are lower. 
 
8.2.9 Ordering 
 
Each center’s pharmacy will order radium-223 as per standard institutional guidelines. 
The product will be delivered as a Patient Ready Dose in a prefilled syringe, ready-to-use 
with a certified activity. Radium-223 is shipped in a lead container and Type A 
radioactive package according to international transportation guidelines for radioactive 
materials.  
 
8.2.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.2.11 Destruction and Return 
 
At the end of the study, unused supplies of radium-223 should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form.  
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Immune biomarker studies  
 
See statistical section for further details on endpoints and laboratory manual for details on 
collection, processing, and shipping. 
 
9.1.1 Bone biopsies 
 
The bone biopsies will be core needle or excisional biopsies. These biopsies will be 
performed per standardized clinical guidelines at Brigham and Women’s Hospital and at 
the corresponding department for participating investigational sites. Tissue will be 
embedded into paraffin. Sites that have been previously irradiated are not permitted.  The 
second biopsy should be done at the same site as the original biopsy when possible. If the 
first biopsy is non-diagnostic, a second pre-treatment biopsy should be performed if safe 
and acceptable to the patient and treating physician. The patient will not be eligible to 
enroll if no tumor tissue can be identified by the pathology team (touch prep evaluation 
will suffice). If the patient is enrolled and it is later determined that the first biopsy is not 
diagnostic or useful towards assessing the primary endpoint of increase in T cell 
infiltrate, then they will not be required to undergo the on-treatment biopsy. If the patient 


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is already on study treatment, they may continue on the study therapy even if no on-
treatment biopsy is obtained. 
 
The on-treatment biopsy should be done after at least 2 doses of radium-223 unless the 
second dose of radium-223 cannot be given due to safety/toxicity. If the latter, it should 
follow the protocol dictated time window (week 8 or within 3 weeks after week 8). If it 
cannot be performed for safety reasons or patient refusal (as long as patient initially 
agreed), it will not be considered a deviation.  
 
Biopsies will be performed by an interventional radiologist under CT or PET-CT 
guidance. Blood samples will be drawn within 30 days of the biopsy to document an 
acceptable coagulation profile (INR < 1.5, PTT < 45, platelets >50,000). Aspirin and/or 
Plavix should be discontinued 5 days prior to the biopsy. On the day of the biopsy, a 
short physical exam will be performed by the radiologist including assessing the patient’s 
general ASA score and airway rating. Informed written consent will be obtained 
following discussion of the risks (bleeding, infection, adjacent tissue injury, and pain) 
and benefits of the procedure. Biopsies will be performed using standard coaxial 
techniques under CT guidance without the administration of intravenous contrast. Several 
bone specimens (when possible, ideally at least 4-6 cores) will be obtained. Samples will 
be given to a dedicated technician present during the procedure for sample processing. 
Conscious sedation will be administered by a trained radiology nurse using small doses 
of Versed and fentanyl titrated to the patient’s level of discomfort. Following the biopsy, 
patients will be observed for 2 hours following their last dose of conscious sedation for 
any complications (severe pain, hematoma, neurologic deficit) prior to departing with a 
chaperone.   
 
See Laboratory Manual for further details. 
 
9.1.2 Collection, Handling, and Shipping of Specimens 
 
For the correlative studies, blood will be drawn and sent to the Fong Lab at UCSF at the 
designated timepoints, please refer to the Laboratory Manual for details. 
 
9.2 
Symptomatic Skeletal Events (SSEs) 
 
SSEs will be defined as the use of external beam radiation to relieve bone pain, 
occurrence of new/symptomatic pathologic fracture, occurrence of spinal cord 
compression, or tumor-related orthopedic surgical intervention (secondary to a 
complication of a bone metastasis).  
 
9.3 
Quality of Life 
 
Quality of life, pain and analgesic use will be measured via the FACT-P (Appendix B), 
Brief Pain Inventory (Short Form) (Appendix C), and analgesic diary (Appendix D) prior 
to treatment, at week 5, 9, and then every 6-8 weeks after week 9 (as schedules differ 
between the two arms), and at treatment progression/off study visit.  


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FACT-P: The FACT-P is a questionnaire with each item scored on a scale of 0-4 with 
higher scores indicating increased symptoms. Scoring instructions are detailed in 
Appendix B.  
 
Brief Pain Inventory (Short Form): The Brief Pain Inventory (short form) is a 15 item 
questionnaire. The BPI allows patients to rate the severity of their pain and the degree to 
which their pain interferes with common dimensions of feeling and function. When 
scoring the Brief Pain Inventory, two scores are calculated: the pain severity and pain 
inference score. The pain severity score is calculated by adding the scores for questions 
3, 4, 5 and 6 and then dividing by 4. This gives a severity score out of 10. The pain 
interference score is calculated by adding the scores for questions 9a, b, c, d, e, f and g 
and then dividing by 7. This gives an interference score out of 10. Changes in mean 
scores for the two domains will be analyzed over time.  
 
Analgesic Use: Participants will record all narcotic analgesic medications taken for pain 
in an analgesic diary provided by the study team during the same assessment intervals in 
which pain scores will be measured. Prior to each interval, a member of the clinical 
research team will pre-populate the diary of each participant with the names and dosages 
of the narcotic medications prescribed, so that patients only have to indicate the number 
of doses taken by the end of each 24 hour period. For each interval, patients’ mean 
narcotics use will be calculated by multiplying the daily dose unit by the number of units 
taken, averaged by the number of days with available data. Changes in narcotic use will 
be qualified as decreased (including discontinued), stable, or increased, based on the 
average daily narcotics use relative to the baseline interval.  
 
Narcotics use will be considered stable if the average daily dose of a given narcotic was 
identical. Equianalgesia calculations will be required to quantify narcotic use if patients 
changed narcotic type or if dosages were changed in patients concomitantly receiving 
different narcotic types. In cases where equianalgesia calculations were required, 
narcotics use will be considered stable if the calculated equivalents were within 5% of the 
baseline dose. 
 
9.4 
Exploratory Bone Response Criteria 
 
Quantitative Bone SPECT/CT  
Substudy to be performed at DFCI only. 
 
Bone scans will be routinely performed as part of the radiologic evaluations for 
measurement of tumor response. SPECT/CT will be obtained at the time of each bone 
scan required per protocol as part of standard of care for anatomic localization of lesions. 
Methods to quantitate bone tracer are not as established as the standardized uptake value 
(SUV) is for FDG-PET/CT, but new methods and software are now available to perform 
quantitation on SPECT/CT (Cachovan et al. EJNMMI; 3:45, 2013). Additional 
processing and quantitative analysis with newer software will be performed as part of 
research to explore if and how quantitative changes in bone tracer uptake on SPECT/CT 
correlate with markers of bone turnover, immune biomarkers, response on standard 


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imaging (CT or MRI). 
 
If SPECT/CT is unable to be completed at screening or at on study timepoints for 
logistical reasons, it will not be considered a protocol violation. 
 
9.5 
Mutations in DNA Repair Genes in Prostate Cancer (to be funded by Bayer) 
 
Prostate cancer represents a broad clinical and biological spectrum ranging from indolent 
tumors to aggressive disease resulting in significant morbidity and mortality. Uncovering 
differences in the genetic makeup of tumors may improve our understanding of its 
clinical heterogeneity. Recent studies have helped define the molecular taxonomy of 
prostate cancer using comprehensive genomic analyses. Robinson et al. demonstrated the 
presence of a potential driver mutation in nearly all metastatic CRPC tumor samples 
which included frequent alterations in the AR (71.3%), PI3K (49%) and DNA damage 
repair (DDR) pathways (22.7%).25  
 
It is estimated that human cells encounter thousands of DNA damaging events on a daily 
basis.26 These events can be mediated by endogenous (deamination and hydrolytic 
reactions, reactive oxygen species, DNA replication errors) and exogenous (ultraviolet 
light, ionizing radiation, alkylating agents and platinum compounds) sources.27,28 
Depending on the causative agent, the extent of DNA damage can range from base 
modifications and nucleotide mismatch to double stranded DNA breaks which is the most 
biologically hazardous form of DNA damage.29 In order to maintain genomic stability 
and compensate for these damaging events, cells have evolved several repair mechanisms 
such as base excision repair (BER), mismatch repair (MMR), nucleotide excision repair 
(NER) and double strand DNA repair pathways which includes homologous 
recombination (HR) and non-homologous end joining (NHEJ).30 HR is the high fidelity 
mechanism preferentially used for repair of double strand DNA breaks and is mediated 
by proteins coded by genes such as BRCA-1, BRCA-2 and Rad52. The importance of 
these genes in maintaining genomic stability is highlighted by the high risk of familial 
breast and ovarian carcinoma and even some prostate cancers associated with germline 
BRCA-1 and BRCA-2 mutations (loss of function of these genes).  
 
In addition to inherited germline mutations, these aberrations can be acquired through 
somatic changes. In advanced prostate cancer, germline and somatic mutations in DNA 
repair mechanisms have been reported in 11.8% and 22.7% of patients respectively.25,31 
In recent study by Annala et al, the presence of DDR mutations was associated with a 
shorter time to the emergence of castration resistance (11.8 months vs. 19.0 months; 
P=0.03) and an attenuated response to AR targeted therapy in castration resistant 
setting.32 However, the presence of impaired DNA repair mechanisms also provides a 
therapeutic opportunity by targeting the inherent genomic instability of these tumor cells. 
Exploiting the biological principle of “synthetic lethality”, the use of PARP inhibitors has 
been associated with impressive responses in patients with advanced ovarian cancer with 
somatic or germline BRCA mutations.33 Mateo et al recently demonstrated the presence 
of somatic or germline alterations in DDR alterations in 33% of patients with CRPC who 
were treated with the PARP inhibitor olaparib in a phase 2 study and that it highly 


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correlated with response.34 Response rates were 33% in the overall study population 
compared to 88% in the cohort with DNA repair alterations, thus suggesting the potential 
role of these abnormalities as predictive biomarkers of response. The impact of these 
mutations on the efficacy of radium-223, which induces double stranded DNA breaks and 
tumor cell death through alpha particles, is unknown. 
 
We hypothesize that tumor cells with germline or somatic mutations in DDR genes will 
be more susceptible to the DNA damaging effects of radium-223. Supporting this 
hypothesis, Steinberger et al recently reported a durable response with 2 courses of 
radium-223 in a patient with a frameshift mutation in BRCA-2.35 Further, the presence of 
impaired DNA repair pathways in the tumor cells has been associated with higher tumor 
mutational load, neo-antigen expression and response to immune checkpoint blockade 
across several solid tumors.36-38 Through this proposed correlative work, we aim to utilize 
whole exome sequencing (WES) to assess the impact of DNA repair and other genomic 
alterations on the clinical efficacy of radium-223 with or without the immune checkpoint 
inhibitor pembrolizumab.  
 
Whole exome and transcriptome sequencing of tumor samples 
 
Pre-treatment and on therapy biopsy specimens with matched germline samples will be 
used for whole exome and transcriptome sequencing in collaboration with the Van Allen 
Laboratory and the Center for Cancer Precision Medicine. Baseline alterations will be 
correlated with clinical outcomes. Induction of on-therapy changes will be characterized 
and correlated with efficacy. To be eligible for DNA isolation, tissue must contain at least 
20% tumor nuclei. The DNA is then analyzed by massively parallel sequencing using a 
solution-phase Illumina hybrid capture kit and an Illumina HiSeq 2500 sequencer at the 
Broad Institute using established methodology. In parallel, capture based whole 
transcriptome sequencing, which can be performed from either frozen or formalin-fixed 
samples will be done on all tumor samples to determine gene expression quantification 
through orthogonal methods, as well as identify fusion products and alternative splicing 
events. Furthermore, RNA analysis through whole transcriptome sequencing will enable 
quantification of immune cell compartments that may be related to specific DNA repair 
mutations (e.g. mismatch repair) and may impact predictions of response, and this 
analysis can enable enrichment of likely pathogenic DNA repair mutations by 
distinguishing those that are present in DNA and also expressed in the RNA.  
 
Circulating tumor derived cf-DNA in advanced prostate cancer 
 
Genomic information derived from tissue based next generation sequencing is being 
increasingly employed in the clinic to guide treatment decisions. While it is an important 
step towards personalized medicine, there are limitations to tissue based sequencing 
assays. There can be significant genomic heterogeneity between the primary tumor and 
the metastatic sites.39 As such, a biopsy of a single disease site might not be 
representative of the overall tumor clone. Further, genomic characteristics of tumors may 
change over the course of treatment with emergence of different resistant mechanisms.40-
42 Although biopsy of a metastatic site can provide genetic information at a given stage in 


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the disease course, it cannot provide insight into how subsequent therapies may induce 
clonal evolution or intrinsic dynamic changes in the biology of the tumor. While serial 
biopsies might accomplish this objective, they subject patients to repeated discomfort and 
increased risk of potential complications adding to the overall morbidity and anxiety of 
the disease.  
 
Analyzing tumor derived cf-DNA in the blood can potentially circumvent the above 
challenges. cf-DNA is composed of fragments of coding and non-coding DNA which are 
released into the circulation during tumor cell apoptosis or necrosis.43 Previous studies 
have shown that compared to normal controls, patients with prostate cancer have 
significantly higher levels of cf-DNA.44 High pretreatment levels of tumor derived cf-
DNA have been associated with poor response to taxane chemotherapy and worse clinical 
outcomes.45 In addition to quantitative changes, cf-DNA has the potential to establish 
pretreatment mutational signatures that may predict resistance or sensitivity to established 
and investigational therapies. Supporting this concept, Salvi et al demonstrated that 
pretreatment copy number gain in AR and CYP17A1 genes detected in cf-DNA samples 
was predictive of poor overall survival and progression-free survival (PFS).46 Further, by 
comparing the genomic alterations at baseline, on treatment, and at the time of disease 
progression, it may be possible to uncover novel mutations, copy number alterations and 
somatic variants which can be acquired as a result of clonal evolution and lead to 
treatment failure.47,48 A major advantage of cf-DNA is that the sample is obtained by a 
simple blood draw and does not require a more invasive tumor biopsy. 
 
Whole genome sequencing of circulating tumor derived cell free DNA 
 
Blood samples will be obtained from patients enrolled in both arms prior to treatment 
initiation (week 1), on therapy at week 5 and week 13, and at the time of disease 
progression. Whole genome sequencing will be performed at 0.1x coverage, which we 
term ultra-low pass whole genome sequencing (ULPWGS). The sequencing information 
derived from ULPWGS will be used to estimate “tumor purity”, which is defined as 
percent of circulating DNA derived from tumor cells in the blood, and to identify copy 
number alterations in the tumor using an adaptation of a probabilistic model, called 
ichorCNA.49 While other algorithms for assessing copy number changes from cf-DNA 
have been described,50,51 ichorCNA has the advantage of accounting for mixtures of cell 
populations to assess for subclonal events and estimating tumor purity. 
 
As this study was added during study enrollment, not all patients will have cfDNA 
analysis performed. Lack of cfDNA samples will not be considered a deviation. 
 
The cfDNA samples will be analyzed by investigators at collaborating institutions, such 
as the Broad Institute, for patients enrolled on this trial. From these samples, the data will 
be submitted to the National Institutes of Health’s Database for Genotypes and 
Phenotypes (dbGaP) and other public databases. Samples and data will be de-identified.  
 
Details regarding obtaining and processing cfDNA can be found in the Laboratory 
Manual. 


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10. STUDY CALENDAR 
 
All baseline evaluations are to be conducted within 42 days prior to treatment initiation.   
 
Assessments must be performed prior to administration of any study agent. On-study 
assessments should be administered within 72 hours of the protocol-specified date but 
prior to study drug administration. Imaging assessments may have a window of +/- 7 
days but must remain on schedule even if doses are being held for toxicity or other 
reasons.   
 
For participants on Arm A, if pembrolizumab is discontinued for toxicity, visits and 
assessments will then follow the schedule for Arm B.  If radium-223 is discontinued, 
visits and assessments will be every 3 weeks at the time of the pembrolizumab dosing. 
The radium-223 visits on Arm A will be discontinued and not considered a protocol 
violation. The quality of life questionnaires and immune studies will be done on the 
pembrolizumab visit closest to their required visit if they had stayed on radium-223 (e.g., 
will be done on week 7 instead of week 8). Imaging assessments will remain the same on 
an every 12 week basis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 15: Required Data Table 
 
A: All baseline evaluations are to be conducted within 42 days prior to treatment initiation. In the event that the participant’s condition 
is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. D1 labs and 
assessments do not need to be performed if have been done within 72hrs prior to study drug dosing.  C1D1 labs do not need to re-meet 
eligibility criteria but do need to meet criteria as detailed in Section 5.2.1. 
 
B: Physical examination should include general description of participant, head, eyes, and throat, chest, abdominal, extremities, 
neurologic, skin, and lymph node examination. Any other evaluation is up to the discretion of the practitioner. It will not be 
considered a violation if the exam is not described as outlined here.  Patient will be seen in clinic the day of any study drug infusion 
(e.g., radium-223 and/or pembrolizumab) 
 
C: Vital signs included blood pressure, heart rate, respiratory rate, body temperature  
Study Calendar 
Pre- 
StudyA 
Wk 
1 
Wk 
4 
(Arm A 
only) 
 
Wk 
5 
 
Wk 
7 
(Arm A 
only) 
Wk 
8 
Wk 
9 
Wk 
10 
(Arm A 
only) 
Wk 
13+ 
(R) 
End of 
TreatmentS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examB  
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Vital signsC 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
ECOG Performance status 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CBC w/diff, pltsD 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Serum chemistryE 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Testosterone 
X 
 
 
 
 
 
 
 
 
 
PSAF 
X 
XF 
 
X 
 
 
X 
 
X 
X 
TSH, Free T4G  
X 
 
X 
X 
 
 
 
 
X 
 
PT/INR, PTTH 
X 
 
 
 
 
 
 
 
 
 
EKG  
X 
 
 
 
 
 
 
 
 
 
PembrolizumabI  
(Arm A only) 
 
X 
X 
 
X 
 
 
X 
X 
 
Radium-223J 
 
X 
 
X 
 
 
X 
 
(X)J 
 
Adverse event evaluationK 
 
X 
X 
X 
X 
 
X 
 
X 
X 
Radiologic evaluation & 
Tumor measurementsL 
X 
 
 
 
 
 
 
 
XL 
 
Correlative immune studiesM 
 
X 
 
X 
 
 
X 
 
X* 
 
Bone biopsyN 
X 
 
 
 
 
X 
 
 
 
 
cfDNAO 
 
X 
 
X 
 
 
 
 
X 
 
FACT-P SurveyP 
 
X 
 
X 
 
 
X 
 
XO 
X 
Brief Pain InventoryP 
 
X 
 
X 
 
 
X 
 
XO 
X 
Analgesic DiaryP 
 
X 
 
X 
 
 
X 
 
XO 
X 
Follow-upQ 
 
 
 
 
 
 
 
 
 
XQ 


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D: CBC with differential should be done before each dose of radium-223 and pembrolizumab. 
 
E: Serum chemistry to include full CMP with sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, albumin. 
Liver function tests to include AST, ALT, total bilirubin and direct bilirubin, alkaline phosphatase.  
 
F: PSAs should be done at baseline, week 1 day 1 (per treating investigator’s discretion), every 4-6 weeks on therapy, and at study 
end. 
 
G: TSH, Free T4 to be done a baseline, week 4 (week 5 for arm B), week 13, and then approximately every 12 weeks.  
 
H: Coagulation factors to include PT and INR.  
 
I: Pembrolizumab will be given by IV every 3 weeks (+/- 3 days) in Arm A only.  
 
J: Radium-223 will be given by IV every 4 (+/- 7 days) weeks for a maximum of 6 doses.  
 
Arm A: Radium-223 will be held after 3 doses. It may be restarted (to complete the final doses up to a maximum of 6 from 
study start) when there is progressive disease in bones as long as there is no new visceral disease.  
 
 
Arm B: Radium-223 will be given as per standard of care monthly for 6 months in a row without breaks except for 
 
toxicity/intolerance as detailed in Section 6.2. 
 
K: Adverse events will be monitored continuously  
 
L: Diagnostic CT chest and CT or MRI of the abdomen and pelvis and bone scan including SPECT/CT should be obtained at baseline 
and every 12 weeks (+/- 7 days). (NOTE: SPECT/CT will be done only at DFCI.)  Scans should remain on an every 12 week schedule 
(+/- 7 days) even if dose delays occur.   
 
M*:  Correlative immune studies: will be obtained and transported overnight at room temperature to the Fong Lab at UCSF. Samples 
for immune studies will be done at week 1 (pre-dose), week 5, week 9, week 13, week 21 and at the time of progression for those 
patients still on study.  
 
N: Bone biopsy: archival tissue is permitted for baseline analysis.  IR guided bone biopsy will be done at week 8 (+3 weeks) after the 
second dose of radium-223. If the second dose cannot be given for safety reasons, biopsy should still be performed within the window 
detailed here. 
 
O: Blood samples for cell free DNA (cf-DNA) will be performed at treatment initiation (week 1, pre-dose), on treatment (week 5 and 
13), and at time of progression. 
 
P: Quality of life, pain and analgesic use will be measured via the FACT-P (Appendix B), Brief Pain Inventory (Short Form) 
(Appendix C), and analgesic diary (Appendix D) prior to treatment, at week 5, 9, then every 6-8 weeks after week 9 (as schedules 
differ between the two arms), and at treatment progression/off study visit. 
 
Q: After progression/treatment discontinuation, follow the participant for survival, receipt of next line therapies, and post-treatment 
SSEs every 6 months until death or 2 years after treatment discontinuation. 
 
R: Arm A study assessments will continue based on the same schedule as detailed for weeks 1-13 when pembrolizumab is given alone 
(e.g., visits, labs, assessments every 3 weeks only). If radium-223 is resumed upon progression, assessment schedule and radium-223 
+ pembrolizumab dosing will resume based on the schedule detailed for weeks 1-13. Arm B study assessments and radium-223 dosing 
will continue based on the same schedule detailed for weeks 1-13 up to 6 doses without breaks except for toxicity/intolerance (Section 
6.2).  
Note: For both arms: Immune studies will follow the schedule detailed in footnote M* 
 
S: End of Treatment visit should occur within 30 days after last study treatment. 
 
 
 
 
 
 
 
 
 


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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 12 
weeks (+/- 7 days).  In addition to a baseline scan, confirmatory scans should also be 
obtained 12 (not less than 6) weeks following initial documentation of progressive 
disease. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1)52 and PCWG223.   
 
11.1.1 Definitions 
 
Eligibility requires lack of measurable disease by RECIST v1.1.  As such, all 
baseline lesions would be considered non-target.  
 
Evaluable Non-Target Disease Response.  Participants who have lesions present 
at baseline that are evaluable but do not meet the definitions of measurable 
disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease:   
 
Note: Patients are not eligible if they have measurable disease for this study.  
 
Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray or 
≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area can still be 
considered measurable if they have grown since the last time of radiation on at 
least 2 subsequent scans.  
 
Malignant lymph nodes:  To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 


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Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all considered non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same participant, these are 
preferred for selection as target lesions. 
 
Non-target lesions.  All bone lesions should be identified as non-target lesions 
and should also be recorded at baseline. Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow up.  
 
11.1.3 Methods for Evaluation of Disease 
 
Imaging studies will be reviewed by independent radiologists at the Tumor 
Imaging Metrics Core at DFCI. Ultimately, all scans will undergo central review 
at DFCI for final response analysis.  However, for eligibility and ongoing 
response assessment while on study therapy, UCSF review will be per 
investigator assessment.  
 
All measurements should be taken and recorded in metric notation using a ruler, 
calipers, or a digital measurement tool.  All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and not more than 
42 days before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT thickness is 5mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size of a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situations 
(e.g. for body scans).   
 


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Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  Furthermore, the availability of MRI is variable globally.  As with 
CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up should be the 
same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If 
markers are initially above the upper normal limit, they must normalize for a 
participant to be considered in complete clinical response.   
 
Cytology, Histology. These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases. 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 
11.1.4 Evaluation of Bone Lesions 
 
Existing bone metastases will be the only lesions in some patients. Because bone lesions 
are notoriously difficult to follow, ‘progression’ in non-target lesions is defined as the 
appearance of 2 new lesions, and, for the first reassessment only, a confirmatory 
scan performed 6 or more weeks later is required that shows a minimum of 2 or more 
additional new lesions (PCWG2 criteria).   
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
PSA.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. It must be representative of overall disease 
status change, not a single lesion increase.     
 


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Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
Definitions of Progression: 
1. Bone Progression: 
Appearance of 2 or more new lesions on bone scan, and, for the first reassessment only, a 
confirmatory scan performed 6 or more weeks later that shows a minimum of 2 or more 
additional new lesions.  The date of progression is the date of the first scan that shows the 
change.  
 
2. Soft Tissue Progression: 
Soft tissue disease progression by modified RECIST v1.1 with additional requirement 
that progression at first assessment be confirmed by a second scan 6 or more weeks later. 
Note that for some treatments, a lesion may increase in size before it decreases. 
 
3. Symptomatic Progression: 
Symptomatic progression is defined as evidence of unequivocal symptomatic or clinical 
progression defined by at least 1 of the following:  
• A marked escalation in cancer-related pain that is assessed by the Investigator to 
indicate the need for other systemic therapy or palliative radiotherapy.  Ignore 
early changes (≤ 12 weeks) in pain or health-related quality of life in absence of 
compelling evidence of disease progression.  Confirm progression of pain or 
health-related quality of life ≥ 3 weeks later  
• An immediate need for initiation of new anticancer treatment or surgical 
intervention for complications due to tumor progression. Palliative radiation is 
allowed while on therapy to combat symptomatic/clinical progression and does 
not require that the patient discontinue study therapy unless treating investigator 
does not believe they are deriving any clinical benefit.   
• A marked deterioration in ECOG performance status to Grade 3 or higher, or  
• It is felt to be in the best interest of the patient to come off study due to clinical 
progression 
 
11.1.5 Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference 
in scanning technique, imaging modality, or findings thought to represent 
something other than tumor (for example, some ‘new’ bone lesions may be 
simply healing or flare of pre-existing lesions). However, a lesion identified 
on a follow-up scan in an anatomical location that was not scanned at baseline 
is considered new and will indicate PD. If a new lesion is equivocal (because 
of small size etc.), follow-up evaluation will clarify if it truly represents new 
disease and if PD is confirmed, progression should be declared using the date 
of the initial scan on which the lesion was discovered. 


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11.1.6 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease): all 
patients in this study will have non-measurable bone only disease  
 
Table 16: Evaluation of Overall Response 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.7 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured 
from the time measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented, or death due to any cause. 
Participants without events reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the baseline 
measurements.  
 
11.1.8 Evaluation of Time to Event Endpoints 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time 
from randomization (or registration) to the earlier of progression or death due to 


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any cause. Participants alive without disease progression are censored at date of 
last disease evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported.  
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization 
(or registration) to death due to any cause, or censored at date last known alive. 
 
11.1.9 Methods for Evaluation of Changes in PSA 
 
Biochemical Response:53 
The laboratory will utilize a consistent method to check serum PSA at baseline, every 
other cycle while on treatment, and at study termination.  
 
PSA decline ≥50% from baseline to 12 weeks of therapy and which has been confirmed 
with a second PSA at ≥ 3 weeks later.  
 
Percent change in serum PSA:23 
The percent change (rise or fall) from baseline at 12 weeks, and separately, the maximal 
change (rise or fall) at any time will be recorded using a waterfall plot. 
 
PSA Progression: 
PSA progression is defined as ≥25% increase and ≥2 ng/mL increase above the nadir or 
baseline value for patients who had a PSA decrease on treatment which is confirmed by a 
second value 3 or more weeks later.   
For patients without a decrease on treatment, PSA progression is defined as ≥25% and a 
≥2 ng/mL after 12 weeks.   
PSA progression must be confirmed at the next study visit 4 weeks later.   
PSA progression alone will not be considered diagnostic of disease progression, and 
will not be used as a reason to discontinue study treatment. 
 
 
12.  
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this 
study. 


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12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data 
and/or data forms to the ODQ according to the schedule set by the ODQ. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this study. The board is chaired by a 
medical oncologist from outside of DF/HCC and has external and internal representation. 
Information that raises any questions about participant safety or protocol performance 
will be addressed by the Overall PI, statistician and study team. Should any major 
concerns arise, the DSMB will offer recommendations regarding whether or not to 
suspend the study. 
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; adverse events and serious adverse events reported by 
category; summary of any deaths on study; audit results; and a summary provided by the 
study team. Other information (e.g. scans, laboratory values) will be provided upon 
request.  
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is an open label phase 2 trial that randomizes 45 mCRPC patients (2:1 ratio) to radium-
223 plus pembrolizumab combination therapy or to radium-223 monotherapy. The primary 
objective is to compare the increase in immune CD8+ and CD4+ T cell infiltration levels 
from baseline to 8 weeks on treatment between the two treatment arms. 
 
Primary Endpoint:  
 
Difference in tissue immune cell (e.g., CD4+/8+ T) infiltration in the bone metastasis 
biopsy specimens from baseline to 8 weeks on treatments in both the combination and 
monotherapy arms.  
 
Secondary Endpoints: 
 
• Safety and Tolerability: grade 3 or higher adverse events that are considered 
treatment related according to NCI CTCAE (version 4.0) 
• Progression-free survival (PFS): is defined as the time from the first dose of study 
drug to the earlier of the first documentation of definitive disease progression [as 


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79 
 
defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) 
and PCWG2] or death due to any cause. Participants alive without disease 
progression are censored at date of last disease evaluation 
 
• Overall survival as defined in 11.1.8 
 
Exploratory Endpoints:    
 
• Clinical-based endpoints 
- 
Changes in PSA   
- 
PSA response: defined as decline ≥50% from baseline to 12 weeks of 
therapy and which has been confirmed with a second PSA at ≥ 3 weeks 
later 
- 
Time to PSA progression as defined in 11.1.9 
- 
Time to normalization of alkaline phosphatase (if initially elevated) 
- 
Time to decrease in alkaline phosphatase (if initially elevated)  
- 
Symptomatic skeletal events (SSEs): Rate of SSEs and time to first SSE  
- 
Changes in osteoblastic activity on bone scan (assessed using the 
quantitative SPECT/CT) 
- 
Changes in quality of life, pain, and analgesic use, and time to 
introduction of analgesics 
 
• Immune-based endpoints 
- 
Quantify the CD8, CD4, and FoxP3+ CD4 (Treg) cell infiltration in the 
bone biopsy specimens, and to subsequently quantify the CD8/Treg and 
CD4/Treg ratios   
- 
Change in circulating T cell clonality 
- 
Induction of IgG antibody response 
- 
Changes in PD-L1 expression and co-regulation of other immune 
checkpoints such as TIM-3, LAG-3, and PD-L2 
- 
Changes in immunosuppressive cell populations and cytokines (e.g., 
MDSCs, Tregs, TGF-β, and iNOS) 
- 
Change in serum chemokines: (e.g., CXCL9, CXCL10) 


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- 
Changes in soluble PD-L1 (Freeman Lab assay) 
• Genomic-based endpoints 
- 
Correlation of DNA damage repair (DDR) mutations in baseline tumor 
samples and circulating cf-DNA with progression-free survival (PFS) 
on radium-223 ± pembrolizumab. 
- 
DDR encompasses genes such as BRCA1, BRCA2, FANCA, 
ATM, PALB2, HDAC2 and CK2 
- 
PFS will be defined as time from randomization to:  
 Appearance of 2 or more new bony lesions compared to 
baseline, confirmed on a repeat bone scan ≥6 weeks later 
 Appearance of new soft tissue lesions on CT/MRI or 
progression of existing ones per RECIST 1.1 criteria  
 Death from any cause 
- 
Prevalence of mutations in DDR genes in tissue or cf-DNA in patients 
with metastatic CRPC treated with Ra-223 
- 
Incidence of novel genomic alterations detected at the time of 
progression as mechanisms of treatment resistance 
- 
Impact of baseline cf-DNA tumor purity (defined as percentage of 
tumor derived circulating DNA; high: >7.5% vs. low: ≤ 7.5%) on 
subsequent PFS     
- 
Change in tumor purity from baseline to weeks 5 and 13  
- 
Impact of change in tumor purity at 13 weeks (increased/stable vs. 
decreased compared to baseline) on PFS  
- 
PSA response (defined as PSA decline ≥50% compared to baseline) and 
overall survival (OS: defined as time from randomization to death from 
any cause) in patients with and without DNA repair mutations on 
radium-223 ± pembrolizumab.  
 
13.2 
Accrual Rate and Study Duration 
 
With two sites participating and an anticipated accrual rate of 4-5 patients per month, we 
expect to enroll 45 patients in approximately 1 to 1.5 years. With an additional 6 months 
of follow-up, the total study duration is expected to be 2 years. If more than 9 patients (6 
on combination arm, 3 on radium arm) have inadequate bone biopsy specimens to assess 
the primary endpoint, patients will be replaced. 


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Table 17: Accrual Targets 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
0 
+ 
8 
= 
8 
Not Hispanic or Latino 
0 
+ 
37 
= 
37 
Ethnic Category: Total of all subjects 
0 
+ 
45 
= 
45 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
8 
= 
8 
Black or African American 
0 
+ 
3 
= 
3 
Native Hawaiian or other Pacific Islander 
0 
+ 
1 
= 
1 
White 
0 
+ 
33 
= 
33 
Racial Category: Total of all subjects 
0 
+ 
45 
= 
45 
 
 
  
 
 
 
13.3 
Stratification Factors 
 
Patients will be stratified based on: 
 
• Baseline alkaline phosphatase <220 or ≥220 
• Volume of bone metastases (high: ≥ 4 bone metastases including one beyond 
the axial skeleton vs. low: <4 bone metastases) 
-Based on CHAARTED (ECOG 3805) criteria24    
 
13.4 
Sample size justification  
 
The study plans to enroll 45 patients to ensure 36 patients to include in the primary analysis 
after taking into consideration that 20% patients may be lost to follow-up or have 
inadequate serum and tissue specimens for analysis. 
 
The sample size justification is based on comparisons between the treatment arms of the 
increase in CD4+ T or CD8+T cell infiltration levels measured in the bone biopsy specimen 
from baseline to 8 weeks. Our primary biological hypothesis is that patients receiving 
pembrolizumab plus radium-223 will have a higher increase in CD8+ and CD4+ T cell 
infiltration from baseline to 8 weeks on treatment than patients treated with radium-223 
alone. While little is known of CD8+ T cell levels in metastatic prostate cancer specimens, 
a 50% to 80% difference between the treatment arms for the increase in CD4+ or CD8+ T 
cells would represent a biologically meaningful treatment effect.  With a total of 36 patients 
with adequate tissue/specimens for analysis, the study would provide 24 patients treated 
with the combination and 12 patients treated with radium-223 monotherapy. There would 
be 91% statistical power to detect a difference of increase in CD4/8 cell infiltration levels 


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between the treatment arms that is 1.2 times the population standard deviation (i.e. an effect 
size of 1.2, defined as the difference as a fraction of population standard deviation) using 
Wilcoxon rank sum test with two-sided type I error α=0.05. This corresponds to a 
hypothesis test for a 70% difference between the two treatment arms of the increase in 
CD4/8 T cell infiltration levels, with a population standard deviation (SD) of 58%. The 
following table provides statistical power to be achieved from a few other scenarios with 
effect size assumptions. 
 
 
Table 18: Statistical power for Wilcoxon rank sum test 
 
Effect size  
(Difference of the increase in CD4/8+ cell infiltration levels 
between arms/SD) 
Evaluable 
Sample sizes 
0.8 
0.9 
1 
1.1 
1.2 
(=.7/0.58) 
100% enrolled  
N1=30, N2=15 
69 
79 
86 
92 
96 
80% enrolled   
N1=24, N2=12 
59 
69 
78 
85 
91 
 
 
13.5 
Safety Monitoring Plan 
 
Give there is no safety data for the combination therapy of pembrolizumab and radium-
223, an early safety monitoring will be conducted to ensure that the combination therapy 
is well tolerated. A rate of targeted grade 3-5 AEs, particularly related to induction of 
immune phenomenon such as pneumonitis, colitis, and severe rash, in excess of 33% with 
combination therapy would be of concern. The safety assessments will be implemented 
after 15 (~50%) of the planned 30 subjects in the combination therapy arm have completed 
12 weeks of combination therapy (including those who discontinued treatment because of 
toxicity), a focused safety review will be conducted. An estimated targeted AE rate with a 
one-sided binomial 90% CI will be constructed.  If 5 or more of the first 15 subjects 
experience the targeted AEs (an observed 33% AEs rate, to have a upper bound of the CI 
<=53%), then the enrollment of combination therapy arm may be suspended pending the 
study team and DSMC review. The following table gives the operating characteristics of 
the early safety stopping; if the true unknown probability of grade ≥3 AEs rate is 40% or 
higher, the probability of observing 5 or more subjects with grade ≥3 AEs will be greater 
than 78.3% at the time of AE assessment. 
 
 
 
 
 
 
 
 
 
Table 19: Operating characteristics of early safety monitoring  


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True/unknown G3+ 
AE rate (%) 
Probability (%) of observing 5 or more ≥ grade 3 AEs  
in 15 subjects 
20 
16.4 
30 
48.5 
40 
78.3 
50 
94.1 
60 
99.1 
 
 
The trial will be reviewed semi-annually by the DF/HCC Data and Safety Monitoring 
Board.  
 
In addition to summarizing all AEs according to type and grade, all grade 4 (or higher) AEs 
will be listed for review.  
 
13.6 
Definition of Analysis Populations 
 
Safety population: All patients who have received at least one dose of radium-223 or 
pembrolizumab will be included in safety assessment. 
 
Primary analysis population: All patients who receive at least one dose of radium-223 
and if in arm A, one dose of pembrolizumab and have bone biopsy assessment at baseline 
and 8 weeks will be included to assess primary, secondary, and exploratory endpoints. 
 
13.7 
Analysis of Primary Endpoints 
 
The extent of immune cell infiltration (in the bone biopsy specimens): The comparison of 
an increase in CD4+ T or CD8+ T cell infiltration levels measured in the bone biopsy 
specimen from baseline and 8 weeks between the treatment arms will use Wilcoxon rank 
sum tests. The difference and the 95% confidence interval will also be provided. 
 
13.8 
Analysis of Secondary Endpoints 
 
Safety and Tolerability: All adverse events recorded during the trial will be summarized 
for the safety population. The incidence of events that is new or worsening from the time 
of first dose of treatment will be summarized according to system organ class term, 
severity (based on CTCAE version 4.0 grade), type of adverse event, and relation to 
study treatment. For the combination therapy, special interests include toxicities related 
to induction of immune phenomenon such as pneumonitis, colitis, and severe rash.  The 
frequency of AEs will be summarized separately according to treatment arms, with 90% 
exact binomial confidence intervals (CI). The proportion of patients in each arm with 
grade 4 or higher AEs will also be reported with an exact binomial 90% CI. 
 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient 
and tabulated by primary system organ class, and type of adverse event. 


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PFS and OS: The distributions of time to PSA progression, PFS and OS will each be 
summarized using the product-limit method of Kaplan-Meier according to treatment 
arms. Median times for each endpoint will be presented with two-sided 95% confidence 
intervals estimated using log(-log(survival)) methodology. Kaplan-Meier estimates of the 
endpoints at 6 or 12 months after treatment initiation may also be presented with two-
sided 95% confidence intervals. 
 
13.9 
Analysis of Exploratory Clinical Endpoints 
 
The endpoints will be summarized descriptively and graphically by treatment assignment. 
Tests for intra-patient changes in values while on combination treatment will use 
Wilcoxon signed-rank for continuous endpoints; categorical endpoints at two timepoints 
will be cross-tabulated and relevant proportions will be reported with confidence 
intervals. Changes in values will also be compared between treatment groups using the 
Wilcoxon rank sum tests for continuous endpoints.  The Kaplan-Meier method will be 
employed to characterize the distributions of time to event endpoints. 
 
Specifically,  
 
Time to PSA progression: the distributions of time to PSA progression will be 
summarized using Kaplan-Meier according to treatment arms. Median times to PSA 
progression will be presented with two-sided 95% confidence intervals.  
 
PSA response: the proportion of patients with a PSA response will be presented with a 
two-sided 95% confidence interval (CI) using exact binominal method according to the 
treatment arms. Change in PSA will also be summarized descriptively according to the 
treatment arms and the changes in PSA will also be compared between treatment groups 
using the Wilcoxon rank sum tests. 
 
Symptomatic skeletal events (SSEs): the proportion of patients with SSEs will be 
presented with a two-sided 95% confidence interval (CI) using exact binominal method 
and the distributions of time to first SSEs will be summarized using Kaplan-Meier plots 
according to the treatment arms.   
 
Quality of life: descriptive statistics at each time point and changes over time will be 
provided for quality of life, pain and analgesic use measures. Mixed models may be used 
to explore the impact of time on quality of life and pain adjusting for treatment arms and 
other relevant factors. 
 
Time to introduction of analgesic use will be summarized using Kaplan-Meier plots 
according to the treatment arms. 
 
 
13.10 Analysis of Exploratory Immune Endpoints 
 


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Will be done at the Fong Lab at UCSF and DFCI Center for Molecular Oncology Core. 
 
We hypothesize that the number of CD8+ and CD4+ T cells will significantly increase 
following anti-PD-1 antibody treatment. IHC will be performed on bone metastasis 
biopsies obtained at baseline and on treatment to quantify tumor infiltration by CD8+ T 
cells, Tregs (FoxP3+ CD4+ cells), and total CD4 T cells (in both normal and tumor tissue).   
We hypothesize that the treatment with Radium-223 will prime T cells and therefore lead 
to changes in the circulating T cell repertoire.  We will assess this by performing TCR 
sequencing of circulating blood on baseline and on treatment blood samples. For each arm, 
the change in circulating TCR between pre-treatment and post- treatment will be assessed 
by calculating the number of unique clonotypes comprising the top 25th percentile of 
cumulative reads after sorting by clone abundance. Repertoire change between sequencing 
experiments will be measured using Morisita’s distance. 
To detect circulating antibodies in sera derived from the pretreatment and on therapy- 
timepoints, spotted antigen arrays will be used. After standard preprocessing of the 
protein array data, Cluster and Treeview software will be used for unsupervised 
clustering of the data with Pearson correlation and complete linkage. For each array, an 
antigen is identified as being detected if its value is above the median. To determine the 
number of up- and down modulated antibodies, the difference in log2 intensity values of 
pretreatment and post-treatment samples will be taken for each patient to identify 
antigens that are detected differentially due to treatment. Number of antibodies with at 
least 2- or 4-fold difference between pretreatment and post-treatment samples will be 
compared between the treatment arms by performing two-sided Wilcoxon rank sum test. 
 
Tumor tissue from each patient’s biopsy will be evaluated by IHC for PD-L1 levels prior 
to administration of the drug. Two independent pathologists who are blinded to the 
patients’ clinical outcomes (e.g., response, survival) will score the percentage of tumor 
cells exhibiting cell-surface staining for PD-L1. PD-L1 positivity is defined per core by a 
5% expression threshold.54,55 Other levels of PD-L1 positivity will be explored. Patients 
with multiple cores will be considered PD-L1–positive if any specimen meets this 
criterion. Similarly, tumor will be stained for other immune checkpoints such as TIM-3, 
LAG-3, and PD-L2. 
 
The bone metastasis biopsies will be evaluated to assess whether increased levels of 
MDSCs, TGF-β, iNOS, arginase, or Tregs which have been linked with T cell 
suppression56 correlate with lower levels of effector T cell infiltrate post PD-1 blockade. If 
so, these may be surrogates for lack of efficacy with this strategy.    
 
The local production of relevant cytokines and chemokines in serum and tumor tissue will 
also be examined using real-time PCR, western analysis, and commercially available 
RNase protection kits. The impact of the agent on the expression of potential 
immunosuppressive molecules such as indoleamine 2,3-dioxygenase, nitric oxide 
synthetase, and arginase in antigen presenting cells will also be evaluated. Post-treatment 
levels will also be characterized. 
 


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For continuous immunologic endpoints, the following table shows the statistical power to 
be achieved for the detectable effect sizes (difference as a fraction of population standard 
deviation) within group comparisons of values and assuming either 100% or 80% of 
patients have paired samples (two-sided α=0.05). 
 
Table 20: Statistical Power assessments for comparisons between two timepoints 
within combination therapy (arm A) 
 
 
Statistical power (%) (bold) 
 
Effect size within arms between two 
timepoints 
Evaluable Sample size 
0.6 
0.7 
0.75 
0.8 
0.9 
If 100% enrolled for analysis 
 
N=30 
61 
75 
80 
85 
92 
If 80% enrolled for analysis 
 
N=24 
52 
65 
71 
76 
85 
  
13.11 Analysis of Exploratory Genomic Endpoints 
 
Mutations in DDR genes can be seen in around 30% of patients with metastatic CRPC.34 
We hypothesize that presence of these mutations would sensitize tumor cells to the DNA 
damaging effects of radium-223 and result in a longer PFS. The study is planned to enroll 
45 patients who will receive radium-223. Assuming 10% will not have adequate tissue 
for sampling, we estimate that we will have adequate samples from at least 40 patients 
available for the correlative study. Using a log-rank test with a one-sided type I error of 
0.15, there is 80% statistical power to detect an improvement in median PFS from 6 
months (patients without DNA repair mutation) to 12 months (patients with a DNA repair 
pathway mutation) corresponding to hazard ratio of 0.50 (Table 21). 
 
Table 21: 
 
The distributions of PFS and OS will each be summarized using the product-limit method 
of Kaplan-Meier according to prevalence of baseline genomic alternations (e.g., with or 
without DNA repair mutation). Median times for each endpoint will be presented with two-
Assumptions: 
• 
N=40 (evaluable samples) 
• 
Median PFS in non-mutated DNA repair group = 6 months 
DDR 
mutation 
prevalence 
Targeted median PFS (mos) 
in patients with patients with 
DDR mutation 
HR 
N (PFS 
event) 
Power 
0.3 
12 
0.5 
36 
0.8 
0.3 
13 
0.46 
36 
0.85 
0.4 
12 
0.5 
36 
0.82 
0.4 
13 
0.46 
35 
0.87 


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sided 95% CI estimated using log(-log(survival)) methodology. Log-rank test will be used 
to compare the median PFSs between the DDR mutation groups. Kaplan-Meier estimates 
of the endpoints at 6 or 12 months after treatment initiation may also be presented with 
two-sided 95% confidence intervals. 
 
For the cfDNA analysis, patients will be dichotomized based on baseline tumor purity 
status into 2 groups: high (tumor purity >7.5%) vs. low (tumor purity ≤ 7.5%). The cutoff 
choice was based on the prior study that demonstrated 7.5% to be the lower limit of 
accurate detection for tumor derived cf-DNA.57 Kaplan-Meier estimates will be used to 
assess the distribution of PFS according to tumor purity status. Medians of time to PFS will 
be shown with two-sided 95% CIs. 
 
An exploratory landmark analysis will be performed and will include all patients who have 
not progressed (no PFS event) by 13 weeks and have available cf-DNA at baseline and 
week 13.  Change in tumor purity from baseline to week 13 on therapy would be used as a 
binary variable (increase/stable tumor purity vs. decreased tumor purity) to assess its 
impact on subsequent PFS. The 13 week time point was chosen to allow for the first 
restaging scans (12 weeks) after initiation of therapy and allow for sufficient exposure to 
pembrolizumab considering prior studies in melanoma and NSCLC have demonstrated a 
median time to response of around 8-12 weeks.58,59 Cox regression model will be employed 
to assess the association of PFS and change in tumor purity, with estimated hazard ratio 
(increase/stable tumor purity vs. decreased tumor purity) and corresponding 95% CI.  
 
The proportion of patients with PSA response (≥ 50% decline from baseline) will be 
presented with a two-sided 95% CI using exact binominal method according to baseline 
genomic alternation (e.g., DDR mutations). Change in PSA will also be summarized 
descriptively according to the genomic alteration groups and the changes in PSA will also 
be compared between genomic alteration groups using the Wilcoxon rank sum tests 
 
Other secondary objectives will be summarized descriptively.  
 
13.12 Reporting and Exclusions 
 
13.12.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
13.12.2 Evaluation of the Primary Efficacy Endpoint 
 
There is no primary efficacy endpoint. 
 
Analyses of secondary efficacy endpoints will be on an intent-to-treat basis. 
Specifically, all eligible participants included in the study must be assessed for 
response/outcome to therapy, even if there are major protocol therapy deviations.   
 
Subanalyses may then be performed on the basis of a subset of participants, 


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excluding those for whom major protocol deviations have been identified (e.g., 
early death due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding 
participants from the analysis should be clearly reported.  If applicable to the 
endpoint, the 95% confidence intervals will be provided.  
 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The 
end of the study is the time point at which the last data items are to be reported, or after 
the outcome data are sufficiently mature for analysis, as defined in the section on Sample 
Size, Accrual Rate and Study Duration. If a report is planned to be published in a peer-
reviewed journal, then that initial release may be an abstract that meets the requirements 
of the International Committee of Medical Journal Editors. A full report of the outcomes 
should be made public no later than three (3) years after the end of the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX A: Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 


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










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APPENDIX C: Brief Pain Inventory (Short Form) 
 
Today’s Date: ____________________Participant Study ID: ____________________ 
Participant Name: _________________Cycle Number: _________________________ 
 
1. Throughout our lives, most of us have had pain from time to time (such as minor 
headaches, sprains, and toothaches). Have you had pain other than these everyday 
kinds of pain today? 
Yes 
No 
2. On the diagram, shade in the areas where your feel pain. Put an X on the area that 
hurts the most. 
3. Please rate your pain by circling the one number that best describes your pain at its 
WORST in the past 24 hours.  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
Pain as bad as you 
can imagine 
4. Please rate your pain by circling the one number that best describes your pain at its 
LEAST in the past 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
Pain as bad as you 
can imagine 
5. Please rate your pain by circling the one number that best describes your pain on the 
AVERAGE. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
Pain as bad as you 
can imagine 
6. Please rate your pain by circling the one number that tells how much pain you have 
RIGHT NOW. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
Pain as bad as you 
can imagine 
7. What treatments or medications are you receiving for your pain? 
 
 
 
 
 
 
 
 
 
 
 




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APPENDIX D: Narcotic Analgesic Diary  
 
 
Participant Name: _________________ 
                   Cycle Number: _________________________ 
 
Study Site Staff: Write in pain medication names, routes, and 
strengths in the columns below. If the route is “other,” specify the 
routine on the line after the “other” check box. List only one type 
and strength of medication on each row. Include all medications 
the participating is taking for pain or that may alleviate pain 
symptoms.  
Study Participant: If on the day you complete this diary you 
start a new medication for pain or change the strength of the pills, 
write the new information on a new row. Do not change the 
information about the medication you have already taken. If the 
drug is given in some other way than orally or via patch, check 
“other” and specify how the drug is given on the line next to the 
“other” check box.  
Pain Medication Use 
Study Participant: Please 
complete this diary for the 24 hour 
period before your study clinic 
visit.  
Record the number of units you 
have taken of each medication 
over the prior 24 hours.  
DATE: _____ / _____ / _____ 
(mm/dd/yy) 
Medication Name 
Route  
(check one box) 
Strength per Unit 
(example 10 mg 
per tablet) 
Number of Units Taken 
 
□ Oral 
□ Patch 
□ Other 
 
 
 
□ Oral 
□ Patch 
□ Other 
 
 
 
□ Oral 
□ Patch 
□ Other 
 
 
 
□ Oral 
□ Patch 
□ Other 
 
 
 
□ Oral 
□ Patch 
□ Other 
 
 
 
□ Oral 
□ Patch 
□ Other 
 
 


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