Clinical trial NCT03211117
Conditions: Thyroid Gland Undifferentiated (Anaplastic) Carcinoma
Sponsor: Mayo Clinic
Start date: 2017-08-14; Completion date: 2019-03-28
Enrollment: 3 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well pembrolizumab, chemotherapy, and radiation therapy work with or without surgery in treating patients with anaplastic thyroid cancer. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as docetaxel and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving pembrolizumab, chemotherapy, and radiation therapy with or without surgery may kill more tumor cells and work better in treating patients with anaplastic thyroid cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the efficacy of pembrolizumab in improving overall survival at 6 months (OS-6) in combination with multimodal therapy involving standard chemo-radiotherapy in anaplastic thyroid cancer (ATC) in comparison to a historical cohort.

SECONDARY OBJECTIVES:

I. To determine safety and tolerance of pembrolizumab with chemoradiotherapy.

TERTIARY OBJECTIVES:

I. To evaluate locoregional control. II. To evaluate progression of distant metastases. III. To evaluate the evolution of the immune profile of circulating immune cells in response to therapy in ATC patents, and to assess potential correlations with outcomes on an exploratory basis.

IV. To evaluate PD-1 and PD-L1 staining in tumor cells and tumor stroma as candidate biomarkers for outcomes.

V. To determine if pre-therapy circulating tumor cell load is associated with outcomes.

VI. To examine associations between outcomes and somatic mutational status as assessed by foundation medicine analysis (for example: presence of BRAF, RAS, P53 and TERT promoter mutations).

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 17 courses after chemoradiation if no residual disease is found or for up to 35 courses after chemoradiation if residual disease is found. After 3 days, patients undergo surgery. Within 42 days of surgery, patients also receive docetaxel IV over 1 hour once weekly (Q1W) and doxorubicin hydrochloride IV Q1W, and undergo intensity-modulated radiation therapy (IMRT) once daily 5 days per week for 6.5 weeks in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 17 courses after chemoradiation if no residual disease is found or for up to 35 courses after chemoradiation if residual disease is found. After 3 days, patients also receive docetaxel IV over 1 hour Q1W and doxorubicin hydrochloride IV Q1W, and undergo IMRT once daily 5 days per week for 6.5 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months until progressive disease and then every 6 months for up to 5 years.

Arms: arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 17 courses after chemoradiation if no residual disease is found or for up to 35 courses after chemoradiation if residual disease is found. After 3 days, patients undergo surgery. Within 42 days of surgery, patients also receive docetaxel IV over 1 hour Q1W and doxorubicin hydrochloride IV Q1W, and undergo IMRT once daily 5 days per week for 6.5 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 17 courses after chemoradiation if no residual disease is found or for up to 35 courses after chemoradiation if residual disease is found. After 3 days, patients also receive docetaxel IV over 1 hour Q1W and doxorubicin hydrochloride IV Q1W, and undergo IMRT once daily 5 days per week for 6.5 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Docetaxel intervention 2: Doxorubicin Hydrochloride intervention 3: Intensity-Modulated Radiation Therapy intervention 4: Laboratory Biomarker Analysis intervention 5: Pembrolizumab intervention 6: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Undergo IMRT intervention 4: Correlative studies intervention 5: Given IV intervention 6: Undergo surgery

Protocol documents:
Prot_SAP_000.pdf: 




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Table of Contents 
Phase 2 study of Pembrolizumab Combined with Chemoradiation Therapy  in Anaplastic Thyroid Cancer
 ...................................................................................................................................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema – Cohort A (surgery) ....................................................................................................................... 4 
Schema – Cohort B (no surgery)................................................................................................................... 5 
1.0 
Background ................................................................................................................................... 6 
2.0 
Objectives ................................................................................................................................... 16 
3.0 
Registration Patient Eligibility .................................................................................................... 17 
4.0  
Test Schedule .............................................................................................................................. 20 
5.0 
Grouping Factor .......................................................................................................................... 22 
6.0 
Registration/Randomization Procedures ..................................................................................... 23 
7.0 
Protocol Treatment ...................................................................................................................... 25 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 28 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 32 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 40 
11.0 
Treatment Evaluation Using RECIST Guidelines ...................................................................... 52 
12.0 
Descriptive Factors ..................................................................................................................... 58 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 58 
14.0 
Body Fluid Biospecimens ........................................................................................................... 61 
15.0 
Drug Information ........................................................................................................................ 63 
16.0  
Statistical Considerations and Methodology ............................................................................... 73 
17.0 
Pathology Considerations/Tissue Biospecimens......................................................................... 78 
18.0 
Records and Data Collection Procedures .................................................................................... 82 
19.0  
Budget ......................................................................................................................................... 83 
20.0 
References ................................................................................................................................... 84 
Appendix I 
ECOG Performance Status ............................................................................................... 88 
Appendix II 
New York Heart Association Classification of Congestive Heart Failure ........................ 89 
Appendix III 
Radiation Therapy Quality Control Guidelines ................................................................ 90 
Appendix IV 
Pembrolizumab ECI Drug-Induced Liver Injury (DILI) .................................................. 95 
Appendix V 
Presentation of Dermatologic Event ................................................................................. 97 
 
 


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Schema – Cohort A (surgery) 
 
Registration 
 
 
↓ 
 
 
Start pembrolizumab q3w* 
(≥3 days before surgery)  
Cycle 1 
 
 
↓ 
 
 
Continue pembrolizumab q3w 
Surgery & recovery 
 
 
↓ 
 
 
Continue pembrolizumab q3w 
RT with chemotherapy 
 
 
↓ 
 
 
Continue pembrolizumab q3w 
 
 
↓ 
 
 
Cross sectional imaging 
 
 
 
 
Residual1 disease: continue 
pembrolizumab q3w for a maximum 
of 35 doses 
 
No residual1 disease: continue 
pembrolizumab q3w for a total of 
17 doses 
 
 
 
 
Observation 1 year 
 
 
↓ 
 
 
At any time: 
Disease Progression 
Patient refusal 
 
 
↓ 
 
 
Event Monitoring 
 
*Cycle = 21 days  
NOTE: all cycles will be based on pembrolizumab given once every three weeks. 
Surgery, chemo and radiation therapy may be given as clinically indicated and any delays are per 
healthcare provider’s discretion. They do not affect the cycle length. (See Section 7.1) 
1Residual disease is defined in Section 11.33  
Generic name:  Pembrolizumab 
(MK-3475) 
Brand name(s): Keytruda® 
Mayo Abbreviation: MK3475 
Availability: Mayo Clinic Pharmacy 
Generic name: Docetaxel 
Brand name(s): Taxotere, Docefrez 
Mayo Abbreviation: TATER 
Availability: Commercial 
Generic name: Doxorubicin 
Brand name(s): Adriamycin 
Mayo Abbreviation: ADR 
Availability: Commercial 


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Schema – Cohort B (no surgery) 
 
Registration 
 
 
↓ 
 
 
Start pembrolizumab q3w 
(≥3 days before ChemoRT)  
(Cycle 1) 
 
 
↓ 
 
 
Continue pembrolizumab q3w 
RT combined with 
chemotherapy 
 
 
↓ 
 
 
Continue pembrolizumab q3w 
 
 
↓ 
 
 
Cross sectional imaging 
 
 
 
 
Residual1 disease: continue 
pembrolizumab q3w for a 
maximum of 35 doses  
 
No residual1 disease: continue 
pembrolizumab q3w for up to 17 
doses 
 
 
 
 
Observation 1 year 
 
 
↓ 
 
 
At any time: 
Disease Progression 
Patient refusal 
 
 
↓ 
 
 
Event Monitoring 
 
*Cycle = 21 days  
NOTE: All cycles will be based on pembrolizumab given once every three weeks. 
Surgery, chemo and radiation therapy may be given as clinically indicated and any delays are per 
healthcare provider’s discretion. They do not affect the cycle length. (See Section 7.1) 
1Residual disease is defined in Section 11.33 
Generic name:  Pembrolizumab 
(MK-3475) 
Brand name(s): Keytruda® 
Mayo Abbreviation: MK3475 
Availability: Mayo Clinic Pharmacy 
Generic name: Docetaxel 
Brand name(s): Taxotere, Docefrez 
Mayo Abbreviation: TATER 
Availability: Commercial 
Generic name: Doxorubicin 
Brand name(s): Adriamycin 
Mayo Abbreviation: ADR 
Availability: Commercial 


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1.0 
Background  
1.1 
Thyroid Cancer Overview 
Thyroid cancer incidence is rising more rapidly than for any other cancer. Thyroid 
cancers include differentiated thyroid cancers (DTC, including papillary and follicular 
variants), medullary thyroid cancer and a highly aggressive variant, undifferentiated or 
anaplastic thyroid cancer (ATC; Figure 1) (Bible and Ryder 2016).  
 
ATC is perhaps the most aggressive human cancer. Historically, fewer than 20% survive 
1 year, median overall survival is ~5 months, and it is almost universally fatal (McIver, 
Hay et al. 2001; Goutsouliak and Hay 2005; Albores-Saavedra, Henson et al. 2007; 
Dandekar, Harmer et al. 2009; Bible, Suman et al. 2012; Mohebati, Dilorenzo et al. 
2014). Doxorubicin is the only FDA approved medication for this malignancy, but has 
poor efficacy [~5% ORR in a randomized study (Shimaoka, Schoenfeld et al. 1985)]. 
Multimodality therapy combining surgery, radiotherapy and cytotoxic chemotherapy 
appears to produce improved survival, but all ATC patients are ultimately expected to 
succumb to their disease, mostly from distant metastatic disease (Bible et al., unpublished 
data, see Section 1.2 and Section 1.5 and Figure 5). More effective therapies are sorely 
needed. 
1.2 
Current treatment strategies for Anaplastic Thyroid cancer 
Treatment for ATC is an oncologic emergency as tumor doubling time can sometimes 
only be in days. Treatment should be instituted expeditiously, and requires input from an 
experienced multidisciplinary team, ideally undertaken at high volume centers. ATC is 
highly aggressive and is highly invasive into neighboring anatomical structures such as 
esophagus and trachea, and therefore represent an emergent threat to airway and to 
esophagus, as well as to vessels and nerves.  
Figure 1. Thyroid cancer molecular pathogenesis 


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Surgical resection is technically difficult in almost all ATC cases. However, there is 
evidence from several retrospective studies that surgical resection may improve survival 
in ATC patients (De Crevoisier, Baudin et al. 2004; Akaishi, Sugino et al. 2011; Sugitani, 
Hasegawa et al. 2014; Kwon, Kim et al. 2016), and it has thus been our practice to aspire 
to resection if feasible. Due to morbidity, however, our practice is generally not to 
undertake laryngectomy, and instead settle for an R1 resection in cases in which para-
laryngeal disease is prominent, as radiotherapy is uniformly administered in our practice 
after surgery in patients who elect an aggressive approach to their disease. This reflects a 
sense that the disease is often systemic and the goal is the rapid onset of chemotherapy 
and radiation therapy, which can be delayed by complex surgical wounds or wound 
complications. 
Radiation therapy is an integral part of the treatment for ATC, both in the setting of 
curative intention and also as part of palliative treatment, even if best supportive care is 
otherwise elected. Multiple institutions over the years have reported their experience with 
multimodal therapy (Aldinger, Samaan et al. 1978; De Crevoisier, Baudin et al. 2004; 
Bhatia, Rao et al. 2010; Akaishi, Sugino et al. 2011; Foote, Molina et al. 2011; Mohebati, 
Dilorenzo et al. 2014). It is unclear if accelerated or hyperfractionated radiation therapy 
incrementally improves outcomes (Heron, Karimpour et al. 2002; Dandekar, Harmer et 
al. 2009), but it has often been demonstrated from retrospective studies that radiation 
dose of >40-50 Gy is associated with better local control and overall survival (Akaishi, 
Sugino et al. 2011). Acute and late toxicity associated with radiation therapy for thyroid 
cancer includes painful mucositis requiring narcotic pain medications, thick secretions, 
altered taste, dehydration, malnutrition, laryngeal edema, cartilage necrosis, esophageal 
stenosis, xerostomia, and feeding tube dependence. Intensity modulated radiation therapy 
may be able to lessen the incidence and severity of these toxicities through lowering the 
daily dose and total dose to the oral cavity, pharyngeal, laryngeal and esophageal mucosa 
and major and minor salivary glands. 
The most common 
chemotherapy 
regimens included 
in chemoradiation 
ATC studies 
included taxanes, 
doxorubicin 
and/or platinum 
agents. 
Doxorubicin is the 
only FDA 
approved agent for 
the treatment of 
ATC and has been 
used with 
radiation 
sensitizing agents 
in multiple studies 
(Aldinger, Samaan 
et al. 1978; Kim 
and Leeper 1983; 
De Crevoisier, 
Baudin et al. 2004; Derbel, Limem et al. 2011; Foote, Molina et al. 2011; Sherman, Lim 
Figure 2. Tumor-associated macrophages in well-differentiated, 
poorly-differentiated and anaplastic thyroid cancer (top panel). 
Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis 
of PD-1 and PDL-1 in thyroid cancer (bottom panel). 


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et al. 2011). Ain et al. demonstrated 53% ORR to paclitaxel in patients with persistent or 
metastatic ATC (Ain, Egorin et al. 2000), but duration of benefit was short. In recent 
studies, docetaxel has been also used in chemoradiation protocols for ATC, and has 
shown some promising efficacy (Troch, Koperek et al. 2010; Foote, Molina et al. 2011; 
Onoda, Kashiwagi et al. 2013; Onoda, Sugitani et al. 2015; Seto, Sugitani et al. 2015). 
Nevertheless, there is no defined standard of care chemotherapeutic agent or regimen to 
be used with radiation therapy. Use of a combination of these agents or any of these 
agents alone is reasonable, with current data favoring use of at least a taxane. 
1.3 
Immune microenvironment of Anaplastic Thyroid Cancer 
Anaplastic thyroid cancers have a high expression of PD-1/PDL-1 (~70%), high 
mutational burden, ~45% rate of BRAF V600 mutation (which promotes a suppressive 
immune environment) and ~10% rate of microsatellite instability; in combination, all of 
these characteristics make ATC a prime target for immunotherapy. 
a. We have previously shown that nearly half of ATC tumor volume is composed of 
tumor-associated monocytes/macrophages (TAMs) (Figure 2) (Ryder, Ghossein et 
al. 2008; Ryder, Gild et al. 2013). Pre-clinical data in thyroid cancer mouse models 
demonstrate that TAMs promote tumor initiation and de-differentiation. Additionally, 
TAMs have potent immunosuppressive effects, particularly through influencing 
increased expression of PD-L1/PD-L2.  
b. Data from human tissues demonstrate increased gene expression of PD-1 and/or PD-
L1 in aggressive thyroid cancers, including ATC (Figure 2) by RT_PCR. 
c. We have also demonstrated increased expression of PDL-1 by immunohistochemistry 
in approximately 80% of the human ATC samples available for testing. There was no 
PD-1 expression in these tumors as well as tumor stroma (Figure 3). Observed 
increased PDL-1 expression was demonstrated by others also (Bastman, Serracino et 
al. 2016), providing the rationale in the form of enhanced target expression for 
proposed pembrolizumab studies.  
d. ATC shows high mutational burden with significant genetic alterations. In a recent 
study, ~70% of the ATC patients demonstrated P53 and TERT mutations (Landa, 
Ibrahimpasic et al. 2016). In another study, similar findings were noted (Kunstman, 
Juhlin et al. 2015). Interestingly, both studies also demonstrated ~10% incidence of 
microsatellite instability (MSIhigh) in ATC (Kunstman, Juhlin et al. 2015; Landa, 
Ibrahimpasic et al. 2016). Both higher mutational burden and MSIhigh status have 
been shown predictive of response to anti-PD-1 therapy in other cancers (Le, Uram et 
al. 2015; Rizvi, Hellmann et al. 2015). 
e. There is now also promising evidence that focal radiation therapy of solid primary or 
metastatic foci of disease, when combined with immune modulating therapies, can 
Figure 3. A. Hematoxylin-eosin stained section of ATC. B. Section of ATC 
showing diffuse positivity for PDL-1, and no staining for PD-1 (C). 
A 
B 
C 




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1.4 
Pembrolizumab 
Cancer cells are known to have the ability to evade immunosurveillance through a variety 
of mechanisms, including: reduced expression of tumor antigens, downregulation of 
MHC class I and II molecules for reduced tumor antigen presentation, secretion of 
immunosuppressive cytokines such TGF-beta, recruitment or induction of 
immunosuppressive cells such as regulatory T cells (Treg) or myeloid derived suppressor 
cells (MDSC), and overexpression of certain ligands (eg, PD-L1) that inhibit the host’s 
existing antitumor immunity(Tang, Wang et al. 2014). Recently, antibodies targeting the 
PD-1/PD-L1 or PD-L2 pathway have shown impressive and durable clinical benefit in 
melanoma, with promising activity emerging in multiple other solid tumors.  
The programmed death 1 (PD-1) pathway is a negative feedback system that represses 
Th1 cytotoxic immune responses that, if unregulated, can damage the host (Nishimura, 
Nose et al. 1999; Nishimura, Okazaki et al. 2001; Chen 2004). It is up-regulated in many 
tumors and in their surrounding microenvironment. Blockade of this pathway with 
antibodies to PD-1 or its ligands has led to remarkable clinical responses in patients with 
many different types of cancer, including melanomas, non–small-cell lung cancer, renal 
cell carcinoma, bladder cancer, and Hodgkin’s lymphoma (Brahmer, Tykodi et al. 2012; 
Topalian, Hodi et al. 2012; Hamid, Robert et al. 2013; Herbst, Soria et al. 2014; Powles, 
Eder et al. 2014; Topalian, Sznol et al. 2014; Ansell, Lesokhin et al. 2015). The 
expression of PD-1 ligands (PD-L1 or PD-L2) on the surface of tumor cells or immune 
cells is an important —but not a definitive— predictive biomarker of response to PD-1 
blockade (Herbst, Soria et al. 2014; Powles, Eder et al. 2014; Taube, Klein et al. 2014; 
Topalian, Sznol et al. 2014; Ansell, Lesokhin et al. 2015). 
Immunotherapeutic strategies aimed at overcoming immunotolerance and improving the 
activation of antitumor T cells represent a new promising therapeutic approach. Among 
them, 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. In a phase I study, 655 patients with advanced 
melanoma were treated with pembrolizumab in four treatment cohorts using one of three 
dose schedules (10 mg/kg every two weeks, 10 mg/kg every three weeks, or 2 mg/kg 
every three weeks). Approximately three-fourths of patients had received prior systemic 
therapies for metastatic disease, including 52 percent who had received prior ipilimumab 
(Duad, Ribas et al. 2015). The overall objective response rate using RECIST criteria and 
central review was 33%. OS at 12 months was 66% and 49% at 24 months. Median PFS 
was 4.4 months, and 35% of patients remained progression-free at 12 months. On 
multivariate analysis, there were no significant differences in outcomes between the three 
dose schedules. Although these studies suggested that PD-L1 positivity correlated with 
increased responsiveness, absence of PD-L1 expression did not preclude a clinical 
response. Treatment-related toxicities were manageable; 83 percent of patients 
experienced one or more treatment-related adverse events. The most common toxicities 
were fatigue, pruritus, rash, diarrhea, and arthralgia (36%, 24%, 20%, 16%, and 16%, 
respectively). Overall 14% of patients experienced Grade 3 or 4 toxicities, the most 
common being fatigue (2%), and there were no treatment-related deaths. 
Two phase III studies, first with ipilimumab-refractory advanced melanoma patients who 
were randomly assigned to pembrolizumab (2 mg/kg every three weeks), pembrolizumab 
(10 mg/kg every three weeks) or chemotherapy (carboplatin plus paclitaxel, paclitaxel 
alone, dacarbazine, or temozolomide per institutional standard) (Ribas, Puzanov et al. 
2015); and second, where pembrolizumab 2 mg/kg and 10 mg/kg doses were compared 
with ipilimumab (Robert, Schachter et al. 2015) in ipilimumab-naïve patients; resulted in 


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US Food and Drug Administration (FDA) approval of pembrolizumab at a dose of 
2 mg/kg every three weeks in September 2014. 
The safety and efficacy of pembrolizumab monotherapy was recently assessed in patients 
with advanced non-small-cell lung cancer (NSCLC) (Garon, Rizvi et al. 2015). Common 
side effects attributed to pembrolizumab were fatigue, pruritus, and decreased appetite. 
Among all patients, ORR was 19.4%, and the median duration of response (DOR) was 
12.5 months.  
Pembrolizumab has since been shown to be efficacious in many solid tumors including, 
head and neck cancer. KEYNOTE-012, a phase 1b trial with recurrent and metastatic 
head and neck cancers, studied the role of single agent pembrolizumab. Only patients 
who were PD-L1+ were enrolled, but later an expansion cohort allowed PD-L1− patients 
to enroll. One hundred and four patients were screened and 60 patients with PD-L1-
positive squamous cell carcinoma of the head and neck were enrolled and treated: 23 
(38%) were HPV-positive and 37 (62%) were HPV-negative. Overall response by central 
imaging review was 18% (eight of 45 patients; 95% CI 8–32) in all patients, and was 
25% (four of 16 patients; 7–52) in HPV-positive patients and 14% (four of 29 patients; 
4–32) in HPV-negative patients (Seiwert, Burtness et al. 2016). Similar results were seen 
for efficacy in the expansion cohort. Another phase 2 study, KEYNOTE-055, enrolled 
recurrent and metastatic head and neck squamous cell carcinoma patients who had failed 
platinum and cetuximab therapy. This study screened 228 patients and enrolled 172. 
Eighty-four percent of the patients had ≥2 lines of therapy and 41% were HPV-positive. 
Again, treatment was well tolerated, and 12% of patients demonstrated grade ≥3 adverse 
events. Overall response rate (ORR) was 22% in patients who had at least 6 months of 
follow up (Bauml, Seiwert et al. 2016).  
Keytruda™ (pembrolizumab) has been approved in the United Stated for the 
treatment of {per Keytruda® (pembrolizumab) package insert 2016}: 
• 
Patients with unresectable or metastatic melanoma 
• 
Patients with metastatic NSCLC whose tumors have high PD-L1 expression 
[(Tumor Proportion Score (TPS) ≥50%)] as determined by an FDA-approved 
test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic 
chemotherapy treatment for metastatic NSCLC 
• 
Patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as 
determined by an FDA-approved test, with disease progression on or after 
platinum-containing chemotherapy 
• 
Patients with EGFR or ALK genomic tumor aberrations should have disease 
progression on FDA-approved therapy for these aberrations prior to receiving 
KEYTRUDA 
• 
Patients with recurrent or metastatic HNSCC with disease progression on or after 
platinum-containing chemotherapy 
1.5 
Multimodal treatment (Mayo Clinic) protocol for treatment of ATC 
As mentioned above, ATC is undifferentiated carcinoma of the thyroid gland that is rare 
(<2% of all thyroid cancers), has historically dire prognosis, and is almost universally 
fatal (Albores-Saavedra, Henson et al. 2007; Bible and Ryder 2016), leading to a 
disproportionately high fraction of thyroid cancer-related deaths (Are and Shaha 2006; 
Neff, Farrar et al. 2008). Randomized clinical trials have seldom been initiated in ATC. 
The combination of rarity of the diagnosis and extremely limited median survival of 4-6 
months, has made it difficult to accrue to randomized clinical trials (McIver, Hay et al. 
2001; Goutsouliak and Hay 2005; Sherman, Lim et al. 2011; Mohebati, Dilorenzo et al. 


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2014). Therefore, to date, doxorubicin, with its very limited efficacy, is the only FDA-
approved agent for the treatment of this malignancy. New treatment strategies and agents 
are sorely needed – but highly challenging to develop and pilot.  
In the absence of currently available randomized data, and considering impediments in 
obtaining such data in the near future, we, at the Mayo Clinic initiated an aggressive 
combined-modality treatment strategy offered to a selective, consecutively treated cohort 
of ATC patients at our institution. We hypothesized that implementation of practice 
change, embracing more uniform and aggressive multimodal therapy (MMT; including 
surgery, combination chemotherapy and intensity modulated radiation therapy) as 
feasible, might lead to improved survival. We carefully select patients for this treatment 
protocol after a thorough multidisciplinary assessment with input from medical oncology, 
radiation oncology and otorhinolaryngology. Consenting patients who are fit, have no 
stage IVC disease, and are expected to have negative margins after resection of the 
thyroid mass, undergo surgery. Combination chemotherapy, preferably weekly dosing, is 
initiated as soon as the patient has convalesced from surgery, or immediately if surgery is 
not planned. Radiation therapy with intensity modulated radiation therapy (IMRT) is 
initiated after careful review and planning by radiation oncologists either as an adjuvant 
or primary therapy. This therapy obviously has its usual expected toxicities such as 
mucositis, dysphagia, pain, nausea, vomiting, weight loss, cytopenias, and neutropenic 
fever. Nearly half of the patients undergo feeding tube placement and require 
hospitalization for complications related to dehydration, mucositis, and pain control. 
However, the protocol is usually completed with close monitoring and initiation of 
mitigating measures promptly for toxicities.  
We have previously published the outcomes of 10 consecutively treated stage IVA and 
IVB ATC patients from our institution and demonstrated that with aggressive combined 
modality treatment median OS was dramatically improved when compared to an 
historical cohort of patients treated at our institution in the preceding 50 years (60 months 
versus 5-6 months)(McIver, Hay et al. 2001; Foote, Molina et al. 2011). We have 
continued to use this MMT approach and have now treated 30 patients with this method. 
Eighteen (18) were treated with best supportive care using a short course of palliative 
radiation (palliative group). We completed the MMT in most patients. In the MMT 
cohort, surgery and chemoradiation therapy was administered to 27 (90%) and 30 (100%) 
patients respectively. Twenty (70%) patients received ≥80% of planned chemotherapy 
doses during radiation therapy.  
Median overall survival (OS) was 21 months, and 1 year survival was 57% (95% CI, 39-
74; Figure 5A). However, it appears that this approach has not improved the survival of 
stage IVC patients. OS of stage IVC patients did not differ in MMT versus the palliative 
cohort (HR, 1.15, 0.4-3.2; P=0.78; Figure 5B). The majority of the patients, including the 
MMT cohort, ultimately died of distant disease. In the MMT cohort, 2 of 27 (7%) 
patients had locoregional relapse and 21 of 27 (77%) had new distant metastasis or 
progression of distant metastasis on follow up.  




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Thus, we hypothesize that a multimodal therapy protocol involving surgery, 
chemotherapy, and radiation therapy coupled with immunotherapy with an anti-PD1 
agent such as pembrolizumab will decrease the incidence of distant metastasis in this 
disease thus improving survival outcomes.  
1.8 
Rationale for correlative studies 
1.81 
Immune phenotyping the peripheral blood 
As not all patients respond to immunotherapeutic approaches, there is 
considerable importance for the elucidation of pre-and on-going therapy 
biomarkers that predict therapeutic responses. Tumor-driven alterations in the 
phenotype and/or trafficking of immune subtypes from the periphery and into 
tumors may be identified by examining the peripheral blood of cancer patients 
(Gustafson, Lin et al. 2014). Comprehensive multi-color FACS analyses of 
whole blood using an established and published protocol has identified distinct 
immune profiles from a broad spectrum of cancer patients that may be unique or 
shared across cancer types, are distinct from healthy controls, and predict 
outcomes. For example, immune phenotyping suggests that a higher ratio of 
CD4+ T cells to CD14+HLAlo/neg monocytes (putative MDSC) in peripheral blood 
independently predicts prolonged survival in cancer patients (Gustafson, Lin et 
al. 2015). Furthermore, increased concentration of peripheral blood 
CD14+HLAlo/neg monocytes may hinder the generation of activated, mature DCs 
in DC vaccine protocols, perhaps contributing to mixed responses in DC vaccine 
trials (Laborde, Lin et al. 2014). Thus, the state of host immunity and the ability 
to induce anti-tumor responses is a critical component for immune checkpoint 
inhibitors. We hypothesize that dynamic immune phenotyping pre- and post 
chemoradiation (combined with pembrolizumab) will serve as a biomarker for 
immune-driven alterations in the tumor that can be used to identify responders 
and/or to identify cell types associated with resistance that can be used to develop 
improved combination immune base strategies to improve overall response rates.  
1.82 
Response evaluations using cytokines, genetics and antithyroid antibodies 
As noted above, there is a strong need to identify potential biomarkers for 
responses to immune-based therapeutics as well as understand toxicities or 
immune-related adverse effects (irAEs) following immune based therapies. 
Analyses of cytokine alternations pre-and post pembrolizumab in the serum may 
reflect relevant immune-related alterations at the tumor site as well as 
systemically. These profiles may be used to better predict patients likely to 
respond to on-going pembrolizumab infusions as well as at risk for potential 
irAEs that may be minimized with early interventions.  
Thyroid autoantibody screens: ATCs often develop from differentiated thyroid 
cancers (DTC), the latter of which are often associated, at least initially, with 
clinical and/or subclinical autoimmune thyroid disease (i.e. an anti-thyroid 
response). In DTCs co-existent with autoimmune thyroid disease, overall 
outcomes are reportedly favorable from limited studies, suggesting the presence 
of an intact anti-tumor immune response. As DTCs progress, however, to PDTC 
and ATCs, tumors become heavily infiltrated with TAMs that, together with 
acquired intrinsic tumor cell genetic alterations, promote an immunosuppressive 
tumor environment and tumor escape from host-mediated anti-tumor control. We 
hypothesize that development of anti-thyroid antibodies could predict the 
responders from non-responders when treated with pembrolizumab. 


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BRAF, P53 and TERT mutations are common in ATC and likely contribute to 
the pathogenicity (Liu, Bishop et al. 2016). Molecular alterations within the 
ATCs may also identify molecular pathways associated with response and/or 
resistance to pembrolizumab (Brauner, Gunda et al. 2016). This may allow future 
studies where they could be targeted to improve anti-PD-1 response and 
overcome resistance. We will therefore interrogate if these somatic mutations are 
associated with the proposed outcomes in a prospective fashion. 
1.83 
Circulating Tumor Cells (CTCs) 
The load and decrease in CTC numbers have been shown to be prognostic 
markers in many cancers including breast (Cristofanilli, Budd et al. 2004; Liu, 
Shields et al. 2009; Smerage, Barlow et al. 2014) and thyroid cancer (Xu, Handy 
et al. 2016). However, data from ATC is lacking and we will aim to 
prospectively collect circulating tumor cells and correlate with outcomes. The 
RareCyte CTC technology is a comprehensive, reproducible and highly sensitive 
dual-platform for collecting, identifying and analyzing CTCs that does not rely 
on EpCAM expression for enrichment. (Campton, Ramirez et al. 2015). This 
platform allows for mechanically precise CTC retrieval, enabling the isolation of 
DNA derived from single or pooled CTCs for advanced genomic analyses 
including the detection of specific mutations and targeted NGS. 
 


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2.0 
Objectives  
2.1 
Primary objective 
To assess the efficacy of pembrolizumab in improving overall survival at 6 months  
(OS-6) in combination with multimodal therapy involving standard chemo-radiotherapy 
in ATC in comparison to an historical cohort. 
2.2 
Secondary Objective 
To determine safety and tolerance of pembrolizumab with chemoradiotherapy. 
2.3 
Exploratory Objectives 
2.31 
To evaluate locoregional control 
2.32 
To evaluate progression of distant metastases 
2.4 
Correlative Research 
2.41 
To evaluate the evolution of the immune profile of circulating immune cells in 
response to therapy in ATC patents, and to assess potential correlations with 
outcomes on an exploratory basis. 
2.42 
To evaluate PD-1 and PD-L1 staining in tumor cells and tumor stroma as 
candidate biomarkers for outcomes.  
2.43 
To determine if pre-therapy circulating tumor cell load is associated with 
outcomes. 
2.44 
To examine associations between outcomes and somatic mutational status as 
assessed by foundation medicine analysis (for example: presence of BRAF, RAS, 
P53 and TERT promoter mutations). 
 


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3.0 
Registration Patient Eligibility 
3.1 
Registration – Inclusion Criteria  
3.11 
Age ≥18 years. 
3.12 
Histological confirmation of, or cytology reported and confirmed, anaplastic 
thyroid cancer in thyroid mass and/or regional lymph nodes. 
NOTE: A diagnosis reported as “poorly differentiated carcinoma consistent with 
anaplastic thyroid cancer” will be accepted. 
3.13 
Prior neck radiotherapy that would preclude re-irradiation. 
3.14 
ECOG Performance Status (PS) 0 or 1 (Appendix I). 
3.15 
The following laboratory values obtained ≤14 days prior to registration: 
• 
Hemoglobin ≥9.0 g/dL 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Total bilirubin ≤1.5 x ULN (except for patients with well-documented 
Gilbert’s Syndrome) 
• 
Aspartate transaminase (AST) ≤3 x ULN 
• 
Creatinine ≤1.5 X ULN  
OR 
• 
Calculated creatinine clearance ≥50 ml/min using the Cockcroft-Gault 
formula below: 
Cockcroft-Gault Equation: 
Creatinine clearance for males =  (140 - age)(weight in kg) 
 
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females =  
(140 - age)(weight in kg)(0.85) 
 
(72)(serum creatinine in mg/dL) 
3.16 
PT/activated PTT ≤1.5 × ULN, unless subject is receiving anticoagulant therapy 
and PT or aPTT is within therapeutic range of intended use of anticoagulants. 
3.17 
Negative pregnancy test done ≤7 days prior to registration, for persons of 
childbearing potential only. 
NOTE: If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
NOTE: Merck requires an additional pregnancy test if eligibility pregnancy test 
is >72 hours prior to first dose. 
3.18 
Persons of childbearing potential must be willing to use an adequate method of 
birth control (as outlined in Section 9.9c) for the course of the study through 
120 days after the last dose of study medication.  
NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred method 
of contraception for the patient. 
3.19a 
Persons able to father a child must agree to use an adequate method of 
contraception (as outlined in Section 9.9c) starting with the first dose of study 
therapy through 120 days after the last dose of study therapy. 
NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred method 
of contraception for the patient. 


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3.19b Provide written informed consent. 
3.19c 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.19d Willing to provide tissue and blood samples for correlative research purposes  
3.2 
Registration – Exclusion Criteria  
3.21 
History of non-infectious pneumonitis that required steroids or current 
pneumonitis. 
3.22 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant persons 
• 
Nursing persons 
• 
Persons of childbearing potential who are unwilling to employ adequate 
contraception 
3.23 
Any autoimmune disease such as inflammatory bowel disease, including but not 
limited to: 
• 
Ulcerative colitis 
• 
Crohn’s Disease 
• 
Rheumatoid arthritis 
• 
Systemic sclerosis 
• 
Systemic lupus erythematosus 
• 
Autoimmune hepatitis 
• 
Other autoimmune disease not listed above 
NOTE: Subjects with autoimmune thyroid disease and diabetes mellitus type I 
will be allowed. 
3.24 
Uncontrolled intercurrent illness including, but not limited to,  
• 
ongoing or active infection,  
• 
symptomatic congestive heart failure,  
• 
unstable angina pectoris,  
• 
cardiac arrhythmia, or  
• 
psychiatric illness/social situations that would limit compliance with study 
requirements. 
3.25 
Other active malignancy ≤6 months prior to registration.  
EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix or 
or prostate cancer confined to prostate gland or coexistent differentiated thyroid 
cancer.  
NOTE: If there is a history of prior malignancy, they must not be receiving other 
treatment for their cancer.  
Ongoing adjuvant hormonal treatment for breast cancer is allowed. 
3.26 
Prior known allergic reaction to pembrolizumab or its excipients. 
3.27 
Untreated brain metastasis. 
3.28 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy.  


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3.29a 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
3.29b Received any live vaccine ≤30 days prior to registration 
3.29c 
Any of the following conditions ≤6 weeks prior to registration: 
• 
Cerebrovascular accident (CVA)  
• 
Admission for unstable angina 
• 
Cardiac angioplasty or stenting or coronary artery bypass graft surgery  
• 
Untreated pulmonary embolism or untreated deep venous thrombosis (DVT)  
• 
Arterial thrombosis  
• 
Class III or IV heart failure as defined by the NYHA functional classification 
system (Appendix II) 
 


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4.0  
Test Schedule 
4.1 
ATC Test Schedule - Cohort A with Surgery 
 
 
Active Monitoring Phase 
 
 
≤14 days prior to Pembro 
Pembro q3w 
Pembro q3w  
Pembro q3w 
30 days after  Obs q3m  
Tests and procedures1 
registration 
(Cycle 
1)2 
(Surgery- rest) during chemoRT post-chemo-RT 
last dose3 
for 1 yr 
Window 
 
±7 
+3 
+3 
±3 
±10 
±14 
History, physical exam, vital signs, weight, ECOG PS  
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test4 
X 
 
 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
Chemistry group5 
X 
X 
X 
X 
X 
X 
X 
Liver function tests6 
X 
X 
X 
X 
X 
X 
X 
Coagulation (PT, aPTT)7 
X 
X 
 
 
 
X 
 
Thyroid function cascade8 
X 
 
 
 
X 
X 
X 
Thyroglobulin by mass spec, thyroglobulin antibodies9 
X 
 
 
 
X 
X 
X 
Urinalysis10 
X 
 
 
 
X 
X 
 
Foundation Medicine (or similar) genomic analyses11 
X 
 
 
 
 
 
 
2D-Echocardiography12 
X 
 
 
 
 
 
 
Tumor imaging and measurement13  
X 
 
 
 
X14 
 
X 
MRI Brain or CT brain 
X 
 
 
 
 
 
 
Research blood specimens (see Section 14.0)R 
 
X 
 
X15 
X16 
X 
 
                                                 
1 Cycle = 21 days; All tests and procedures are clinically indicated, unless noted with an R to indicate funding by research. 
2 Laboratory tests (except research blood specimen collection) conducted by sites outside of Mayo Clinic are acceptable if conducted within 7 days of the start of Cycle 1 
3 All patients will be followed for aftereffects of immunotherapy for the duration of their care. 
4 For persons of childbearing potential only; must be done ≤7 days prior to registration. 
5 Sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium 
6 AST, alkaline phosphatase, total and direct bilirubin 
7 Coagulation is required at baseline, then as clinically indicated 
8 Thyroid function testing every 6 weeks to monitor effects of pembrolizumab or as clinically indicated. 
9 Thyroglobulin testing can be done every 6 weeks or as clinically indicated. 
10 Urinalysis for protein, glucose, blood every 6 weeks or as clinically indicated 
11 Optional, can be conducted at any time while on study 
12 Only if results are not available for a 2D Echocardiography test conducted within 3 months prior to registration 
13 PET/CT or MRI neck or CT neck + CT chest and abdomen and pelvis; initial tumor imaging ≤14 days prior to registration; Use same imaging technique throughout the study 
14 Imaging is to be performed before first dose of pembrolizumab and after chemoRT is done; then q9wks or as clinically indicated during treatment, and q3mo during observation. 


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Active Monitoring Phase 
 
 
≤14 days prior to Pembro 
Pembro q3w 
Pembro q3w  
Pembro q3w 
30 days after  Obs q3m  
Tests and procedures1 
registration 
(Cycle 
1)2 
(Surgery- rest) during chemoRT post-chemo-RT 
last dose3 
for 1 yr 
Research tissue specimens (see Section 17.0)R 
X 
 
X 
 
X17 
X18 
 
 
 
4.2 
ATC Test Schedule - Cohort B without Surgery 
 
 
Active Monitoring Phase 
Tests and procedures19 
≤14 days prior  Pembro 
Pembro q3w  
Pembro q3w 
30 days after  Obs q3m 
to registration 
(Cycle 
1)20 
during chemoRT 
post-chemo-RT 
last dose 
1 yr 
Window 
 
±7 
±3 
±3 
±10 
±14 
History, physical exam, vital signs, weight, ECOG PS 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
Pregnancy test21 
X 
 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
Chemistry group22 
X 
X 
X 
X 
X 
X 
Liver function tests23 
X 
X 
X 
X 
X 
X 
Coagulation (PT, aPTT) 
X 
X 
 
 
X 
 
Thyroid function cascade24 
X 
 
 
X 
X 
X 
Thyroglobulin by mass spec, thyroglobulin antibodies25 
X 
 
 
X 
X 
X 
Urinalysis26 
X 
 
 
X 
X 
 
                                                                                                                                                                                                                         
15 One time prior to Cycle 3 Day 1 of pembrolizumab 
16 One time prior to first post-chemoRT dose of pembrolizumab 
17 Optional, only on first pembro cycle post-chemo-RT if clinical biopsy performed 
18 Optional, if clinical biopsy performed 
19 Cycle = 21 days; All tests and procedures are as clinically indicated, unless noted with an R to indicate funding by research 
20 Laboratory tests conducted by sites outside of Mayo Clinic are acceptable if conducted within 7 days of the start of Cycle 1 
21 For persons of childbearing potential only; must be done ≤7 days prior to registration 
22 Sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium 
23 AST, alkaline phosphatase, total and direct bilirubin 
24 Thyroid function testing every 6 weeks to monitor effects of pembrolizumab or as clinically indicated. 
25 Thyroglobulin testing can be done every 6 weeks or as clinically indicated. 


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Amendment 1 
Version date: 21Nov2017 
 
 
Active Monitoring Phase 
Tests and procedures19 
≤14 days prior  Pembro 
Pembro q3w  
Pembro q3w 
30 days after  Obs q3m 
to registration 
(Cycle 
1)20 
during chemoRT 
post-chemo-RT 
last dose 
1 yr 
Foundation Medicine (or similar) analyses27 
X 
 
 
 
 
 
2D-Echocardiography28 
X 
 
 
 
 
 
Tumor imaging and measurement29  
X 
 
 
X30 
 
X 
MRI Brain or CT brain 
X 
 
 
 
 
 
Research blood specimens (see Section 14.0)31,R 
 
X 
X32 
X33 
X 
 
Research tissue specimens (see Section 17.0) 34,R 
X 
 
 
X35 
X36 
 
 
4.3 
Event Monitoring/Survival Follow-up 
 
Event Monitoring Phase1 
q. 3 months 
until PD 
At PD 
After PD  
q. 6 months 
Death 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
 
5.0 
Grouping Factor  
Cohort: A (with surgery) vs. B (no surgery) 
 
 
                                                                                                                                                                                                                         
26 Urinalysis for protein, glucose, blood every 6 weeks or as clinically indicated 
27 Optional, can be conducted at any time while on study 
28 Only if results are not available for a 2D Echocardiography test conducted within 3 months prior to registration 
29 PET/CT (or MRI neck or CT neck and CT chest + abdomen and pelvis); Initial tumor imaging ≤14 days prior to registration; Use same imaging technique throughout the study 
30 Imaging is to be performed before first dose of pembrolizumab after chemoradiation and then every 9 weeks or as clinically indicated during protocol treatment, and every 
3 months during observation period. 
31 Blood specimens will be collected and submitted per Section 14.0 
32 One time prior to Cycle 3 Day 1 of pembrolizumab 
33 Only on first post chemoRT cycle 
34 Tissue specimens must be collected and submitted per Section 17.0 
35 Optional, only on first post-chemoRT cycle if clinical biopsy performed 
36 Optional if clinical biopsy performed 


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6.0 
Registration/Randomization Procedures 
6.1 
Registration 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the remote registration/randomization application. The registration/randomization 
application is available 24 hours a day, 7 days a week. Back up and/or system support 
contact information is available on the Web site. If unable to access the Web site, call the 
MCCC Registration Office a
 between the hours of 8 a.m. and 5:00 p.m. 
Central Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the 
MCCC web page
 and detail the process for 
completing and confirming patient registration. Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions. It is the responsibility of the individual and 
institution registering the patient to confirm the process has been successfully completed 
prior to release of the study agent. Patient registration via the registration/randomization 
application can be confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office
. If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
6.2 
Verification 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval of the study 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (
 
If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.4 
Correlative studies 
6.41 
A mandatory translational research component is part of this study; the patient 
will be automatically registered onto this component (Sections 3.19d, 14.0, 17.0). 
6.42 
An optional correlative research component is part of this study, there will be an 
option to select if the patient is to be registered onto this component (see Section 
17.0) : 


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Amendment 1 
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Patient has/has not given permission to give his/her tissue sample for research 
testing. 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research of cancer at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
6.5 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic under the supervision of a 
medical oncologist or radiation oncologist  
6.6 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
6.7 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.8 
Baseline symptoms 
All required baseline symptoms (see Section 10.0) must be documented and graded. 
6.9a 
Study drug is available on site  
 
 


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7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
7.11 
Treatment medication table 
Agent 
Dose Level 
Route 
ReRx 
Pembrolizumab 
200 mg 
IV 
q3w 
Cycle = 21 days 
Note: All cycles will be based on pembrolizumab given once every three weeks. 
Chemo and radiation therapy may be given as clinically indicated and any delays 
are per physicians’ discretion. Such delays do not affect the cycle length of 
pembrolizumab. 
7.12 
Cycle 1 - Prior to surgery (Cohort A) or chemoradiation (Cohort B) 
Agent 
Dose Level 
Route 
ReRx 
Pembrolizumab 
200 mg 
IV 
q3w 
All enrolled patients will undergo treatment with one dose of pembrolizumab 
200 mg IV once as soon as possible, at least ≥3 days prior to undergoing surgical 
resection or starting radiation therapy.  
NOTE: Patients will sometimes require emergency debulking surgery for 
impending airway obstruction or any threatening disease to vital structures in 
neck including vasculature and can undergo surgery emergently within those 3 
days. If no surgery is planned or indicated, subjects should proceed with 
chemoradiation, see Section 7.14 below. 
7.13 
Surgery for Cohort A – per clinical indications 
Agent 
Dose Level 
Route 
ReRx 
Pembrolizumab 
200 mg 
IV 
q3w 
Surgery should occur approximately 3 days after pembrolizumab dose given in 
Cycle 1. Surgical recovery period is expected to be approximately 42 days or 
less.  
Pembrolizumab dosing should continue every 3 weeks throughout this period. 
7.14 
During chemoradiation– per clinical indications 
 
Agent 
Dose Level 
Route 
ReRx 
Pembrolizumab 
200 mg 
IV 
q3w 
 
 
 
 
AND 
 
Suggested 
Chemotherapy 
Agents 
Dose Level 
Route 
ReRx 
Docetaxel 
20 mg/m2  
IV 
q1w 
Doxorubicin 
20 mg/m2 
IV 
q1w 
OR 
 


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Amendment 1 
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Suggested 
Chemotherapy 
Agents 
Dose Level 
Route 
ReRx 
Docetaxel 
60 mg/m2 
IV 
q3w 
Doxorubicin 
60 mg/ m2 
IV 
q3w 
Pembrolizumab 200 mg IV every 3 weeks will be continued throughout 
chemoradiation therapy. Pembrolizumab can be given concurrently on the days 
of chemotherapy.  
All patients will undergo the standard chemoradiation therapy administered at 
Mayo Clinic which includes radiation therapy concurrently administered with 
combination chemotherapy (doxorubicin plus docetaxel, 20 mg/m2 each, weekly, 
or 60 mg/m2 every 3 weeks with growth factor support at the discretion of 
treating provider).  
Chemotherapy will stop once chemoradiation is completed. Only pembrolizumab 
will continue in post-chemoradiation phase as per Section 7.16 below. 
7.15 
Radiation Therapy – per clinical indications 
Radiation therapy will be administered daily, 5 days a week for 6.5 weeks, 33 
treatments, total dose 66 Gy to gross disease or high risk postoperative regions (2 
Gy per treatment) and 59.4 Gy to areas potentially harboring subclinical disease 
(1.8 Gy per treatment). If there is no gross disease (postoperative adjuvant 
setting), the dose will be 60 Gy in 30 treatments to the operative volume (2 Gy 
per treatment) and 54 Gy in 30 treatments to areas potentially harboring 
subclinical disease (1.8 Gy per treatment).  As indicated, the first few treatments 
may be administered using highly conformal 3D radiation therapy while waiting 
for insurance approval for IMRT, or while waiting for an IMRT plan.  In cases 
where IMRT coverage is denied by the insurer, highly conformal 3D radiation 
therapy techniques may be utilized for the entire treatment.  BID treatments (≥6 
hours between treatments) or weekend treatments are allowed to compensate for 
treatment breaks. 
7.16 
Post-chemoradiation 
Agent 
Dose Level 
Route 
ReRx 
Pembrolizumab 
200 mg 
IV 
q3w 
Following the multimodality therapy pembrolizumab at 200 mg IV every 3 
weeks will continue to be administered per disease status given below: 
7.161 If no residual disease is found, pembrolizumab will be administered for a 
total of 17 doses or progressive disease or unacceptable adverse events, 
whichever is first 
7.162 If there is residual disease, pembrolizumab will be administered for a 
maximum of 35 doses or until progressive disease or unacceptable 
adverse events; whichever is first. 
NOTE: Residual disease is defined in Section 11.33. 
7.2 
Description of chemoradiation – per Mayo Clinic clinical care standards for ATC 
7.21 
Chemotherapy with doxorubicin and docetaxel 


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Amendment 1 
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Intravenous chemotherapy with 20 mg/m2 of doxorubicin and docetaxel each will 
be administered every week during chemoradiation therapy along with 
pembrolizumab as mentioned in Section 7.14 above. Both chemotherapy and 
radiation will commence as soon as the possible with regards to tissue healing 
and per surgeon’s recommendations.  
Alternatively, chemotherapy also could be administered every three week at 60 
mg/m2 of doxorubicin and docetaxel each (with growth factor support). This may 
be sometimes be required to achieve rapid response, and is at the discretion of 
treating provider. 
7.22 
Radiation therapy with IMRT 
Radiation therapy will be administered daily, 5 days a week for 6.5 weeks, 33 
treatments, total dose 66 Gy to gross disease or high risk postoperative regions (2 
Gy per treatment) and 59.4 Gy to areas potentially harboring subclinical disease 
(1.8 Gy per treatment). If there is no gross disease (postoperative adjuvant 
setting), the dose will be 60 Gy in 30 treatments to the operative volume (2 Gy 
per treatment) and 54 Gy in 30 treatments to areas potentially harboring 
subclinical disease (1.8 Gy per treatment).  As indicated, the first few treatments 
may be administered using highly conformal 3D radiation therapy while waiting 
for insurance approval for IMRT, or while waiting for an IMRT plan.  In cases 
where IMRT coverage is denied by the insurer, highly conformal 3D radiation 
therapy techniques may be utilized for the entire treatment. BID treatments (≥6 
hours between treatments) or weekend treatments are allowed to compensate for 
treatment breaks. Radiation therapy  must begin with combination chemotherapy 
per standard clinical practice. If radiation therapy is delayed, chemotherapy can 
begin up to 7 days prior to radiation therapy. Radiation Dose and planning 
suggestions for IMRT are in Appendix III. 
7.23 
RT Quality Assurance Reviews  
The study co-chair, 
 will perform RT Quality Assurance 
Reviews per clinical standard of care. 
7.3 
Return to consenting institution 
For this protocol, the patient must return to the consenting institution for evaluation 
during treatment per the study calendar in Section 4.0 and every 3 months during 
observation (Active Monitoring Phase). 
7.4 
Treatment by local medical doctor (LMD) 
Treatment by a local medical doctor (LMD) is not allowed. 
 
 


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8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in the following tables until individual treatment tolerance can 
be ascertained. Thereafter, these modifications should be regarded as guidelines to produce 
mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on 
adverse events observed since the prior dose. 
→ ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current version 4.0* 
unless otherwise specified   
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
8.1 
Dose modification for Radiation Therapy 
Radiation should be continued unless the patient has serious life threatening 
complications. Please contact study co-chair 
 if 
questions. 
8.2 
Dosage modifications for pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology. These AEs 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. See 
Section 9.0 for supportive care guidelines, including use of corticosteroids. 
Table 8.21 
Dose Modification Guidelines for Drug-Related Adverse Events for 
Pembrolizumab 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Hold 
Treatment 
for Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Gastrointestinal 
disorders 
Diarrhea or 
Colitis 
2-3 
AE resolves to Grade 0-
1 
AE 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 
Investigations 
AST, or ALT, or 
Blood bilirubin 
 
2 
AE resolves to Grade 0-
1 
AE does not resolve within 12 
weeks of last dose. 
 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
pembrolizumab 
Metabolism and 
nutrition disorders 
Glucose 
intolerance (Type 
1 diabetes 
mellitus [if new 
onset]) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab for 
new onset Type 1 
diabetes mellitus or 
Grade 3-4 
hyperglycemia 
associated with evidence 
of beta cell failure 
Resume pembrolizumab when 
patients are clinically and 
metabolically stable. 


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CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Hold 
Treatment 
for Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Endocrine disorders 
Endocrine 
disorders – Other, 
specify: 
Hypophysitis 
2-4 
AE resolves to Grade 0-
1. Therapy with 
pembrolizumab can be 
continued while 
endocrine replacement 
therapy is instituted 
AE 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 
Endocrine disorders 
Hyperthyroidism 
3 
AE resolves to Grade 0-
1 
AE 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 
Endocrine disorders 
Hypothyroidism 
2 
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab 
can be continued while thyroid 
replacement therapy is 
instituted 
General disorders and 
administration site 
conditions 
Infusion related 
reaction 
2b 
AE resolves to Grade 0-
1 
Permanently discontinue if AE 
develops despite adequate 
premedication  
 
 
3-4 
Permanently discontinue 
Permanently discontinue 
Respiratory, thoracic 
and mediastinal 
disorders 
Pneumonitis 
1 
AE resolves to Grade 0 
AE 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 
 
 
2-4 
Permanently discontinue 
Permanently discontinue 
Renal and urinary 
disorders 
Acute kidney 
injury or Chronic 
kidney disease  
(e g Renal failure 
or Nephritis) 
2 
AE resolves to Grade 0-
1 
AE 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 Adverse 
Eventsc 
3 
AE resolves to Grade 0-
1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT 
increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients 


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should be discontinued. 
b 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. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion. Permanently discontinue study drug for persistent Grade 2 adverse reactions for which 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
8.21 
Other instructions for pembrolizumab 
If pembrolizumab-related toxicity does not resolve to Grade 0-1 within 12 weeks 
after last administration of study drug, study therapy discontinuation is 
recommended. With Investigator agreement, patients with a laboratory adverse 
event still at Grade 2 may continue in the study only if asymptomatic and 
controlled. 
For patients who experience a recurrence of the same severe AEs listed above 
with rechallenge of pembrolizumab, a consultation with the Investigator will 
occur to determine whether the patient should continue in the study. A patient 
who experiences the same SAE of the same NCI CTCAE grade or higher with 
rechallenge of pembrolizumab must discontinue pembrolizumab immediately. 
Reduced dose of pembrolizumab dose (ie, below 200 mg) will not be 
administered. 
8.3 
Dose modifications for doxorubicin and docetaxel 
8.31 
Suggested dose levels for chemotherapy* 
Dose Level 
Doxorubicin 
Docetaxel 
Starting Dose 
20 mg/m2 
weekly  
or 
 60 mg/m2 
every 3 weeks 
(with growth 
factor support) 
20 mg/m2 
weekly  
or 
 60 mg/m2 
every 3 weeks 
(with growth 
factor support) 
-1 
-25% 
-25% 
-2 
-50% 
-50% 
*These levels are guidelines only 
8.32 
Chemotherapy table of events and modifications for Doxorubicin and Docetaxel 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENTa 
ACTION 
Blood and lymphatic 
disorders 
Febrile neutropenia 
(fever without 
clinically or 
microbiologically 
documented 
infection) [ANC 
<1.0 X 109 C/L] 
fever ≥38.3oC) 
Doxorubicin 
and/or 
Docetaxel 
Delay chemotherapy by 1 week until ANC 
recovers to Grade 0-2 and until fever 
resolves. 
Reduce dose by 25% or more for 
subsequent cycles. 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENTa 
ACTION 
Cardiac Disorders 
Left ventricular 
systolic 
dysfunction 
Doxorubicin 
and/or 
Docetaxel 
Grade 3 discontinue doxorubicin, and 
continue docetaxell with careful 
monitoring; grade 4 discontinue 
chemotherapy. 
 
Atrioventricular 
block first degree 
Doxorubicin  Grade ≥3 Discontinue doxorubicin, 
continue Docetaxel  
Gastrointestinal 
disorders 
Vomiting 
≥Grade 3 
Doxorubicin 
and/or 
Docetaxel 
If not controlled with optimal 
medicationReduce dose by 25% and use 
reduced level for subsequent cycles 
 
Allergic reaction 
Grade 1 
(eg, mild flushing, 
rash, pruritis) 
Doxorubicin 
and/or 
Docetaxel 
Stop infusionAfter recovery restart the 
infusion at a rate of 20 ml/h for 15 
minutes then 50 ml/h for 15 minutes then, 
if no further symptoms, at full dose rate 
until infusion is complete 
Immune system 
disorders 
Allergic reaction 
Grade 2-3 
(e.g. moderate rash, 
flushing, mild 
dyspnea, chest 
discomfort, mild 
hypotension) 
Doxorubicin 
and/or 
Docetaxel 
Stop infusionGive IV antihistamine 
(diphenhydramine 50 mg IV), IV H2-
receptor antagonist (famotidine 20 mg IV) 
and steroid (dexamethasone 10 mg IV) 
After recovery of symptoms resume 
docetaxel infusion at a rate of 20 ml/h for 
15 minutes then 50 ml/h for 15 minutes 
then, if no further symptoms, at full dose 
rate until infusion is complete 
 
Anaphylaxis 
(e.g. one or more of 
the following): 
respiratory distress 
requiring treatment, 
generalized urticaria, 
angioedema, 
hypotension 
requiring therapy) 
Doxorubicin 
and/or 
Docetaxel 
Stop infusiongive IV antihistamine 
(diphenhydramine 50 mg IV), IV H2-
receptor antagonist (famotidine 20 mg IV) 
and steroid (dexamethasone 10 mg IV) 
Add epinephrine or bronchodilators if 
indicated, report as an adverse event 
Discontinue doxorubicin and/or docetaxel. 
Investigations 
Neutrophil count 
decreased 
≥Grade 3 (ANC 500 
to <1000/mm3) 
Doxorubicin 
and/or 
Docetaxel 
Delay chemotherapy by 1 week until 
recovery to Grade 0-2 
Consider reducing dose by 25% for 
subsequent cycles 
 
Platelet count 
decreased 
≥Grade 2 (<75 x 
109/L) 
Doxorubicin 
and/or 
Docetaxel 
Delay chemotherapy by 1 week until 
recovery to Grade 1Consider reducing 
dose by 25% for subsequent cycles 
Investigations 
Bleeding ≥Grade 3 
or requiring 
≥2 platelet 
transfusions 
Doxorubicin 
and/or 
Docetaxel 
Delay chemotherapy by 1 week until 
bleeding recovers to Grade 0-1 
Permanently discontinue chemotherapy, 
or reduce dose by 25% or more for 
subsequent cycles 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENTa 
ACTION 
Nervous system 
disorders 
Peripheral motor 
neuropathy 
Grade 2 
Docetaxel 
Reduce dose by 25% and use reduced 
level for subsequent cycles 
 
Peripheral motor 
neuropathy 
Grade 3 or higher 
Docetaxel 
Discontinue docetaxel 
All other non-
hematologicb 
≥Grade 3 
Doxorubicin 
and/or 
Docetaxel 
Discontinue chemotherapy, or reduce dose 
by 25% or more and use reduced dose for 
subsequent cycles 
a If a drug is held, omitted, discontinued or dose-reduced, it is the physician’s discretion to apply the 
modification to one or both cytotoxic drugs, and the decision should depend on the nature and 
severity of the particular adverse event and its likely causal relation to the agent. 
b For adverse effects ≥Grade 3 commonly associated with radiation such as radiation dermatitis, dry 
mouth, mucositis, thick secretions/saliva, loss of  taste, weight loss, loss of appetite dose 
modifications for chemotherapy will be at the discretion of the treating physician. 
 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
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. The treatment guidelines are intended to be applied 
when the investigator determines the events to be related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). Refer to Section 8.2 
for dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. 
9.2 
Blood products and growth factors  
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Vol 24, No 18 (June 
20), 2006: pp. 2932-2947. 
9.21 
Neutropenia 


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Prophylactic use of colony-stimulating factors including Granulocyte Colony-
Stimulating Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage 
Colony-Stimulating Factor GM-CSF is not allowed in this study. Therapeutic use 
of G-CSF is allowed in patients with Grade 3-4 febrile neutropenia. 
9.22 
Anemia 
Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia, but should be clearly noted as concurrent medications. 
9.23 
Thrombocytopenia 
Transfusion of platelets may be used if clinically indicated. ITP should be ruled 
out before initiation of platelet transfusion. 
9.3 
Anti-infectives 
Patients with a documented infectious complication should receive oral or IV antibiotics 
or other anti-infective agents as considered appropriate by the treating Investigator for a 
given infectious condition, according to standard institutional practice. 
9.4 
Corticosteroids 
Patients may continue on steroid inhalation therapy. Systemic corticosteroids are known 
immunosuppressive agents that can mitigate the effects of pembrolizumab. Steroids 
should be generally reserved to treat side effects of pembrolizumab. Steroids can be used 
as primary prevention of nausea per institutional guidelines, but steroid doses should be 
reduced in subsequent cycles if nausea/vomiting is absent or very mild (see Section 9.5). 
9.5 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. Nausea and 
vomiting should be treated aggressively, and consideration should be given to the 
administration of prophylactic antiemetic therapy according to standard institutional 
practice. Patients should be strongly encouraged to maintain liberal oral fluid intake. 
Volume depletion should be corrected before initiation of study drug. 
If no or minimal nausea/vomiting is reported after first dose of chemotherapy, 
investigators are strongly encouraged to reduce the dose of dexamethasone to 10 mg 
as pre-treatment anti-emetic dosing on Day 8. In addition, if nausea/vomiting 
continues to be a minimal issue, investigators are strongly encouraged to 
progressively decrease the pre-treatment dose of dexamethasone in subsequent 
doses (eg, 8 mg, 6 mg, 4 mg, 2 mg, or zero). 
9.6 
Anti-diarrheals 
Patients should be monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation 
(such as peritoneal signs and ileus). In symptomatic patients, infectious etiologies should 
be ruled out, and if symptoms are persistent and/or severe, endoscopic evaluation should 
be considered. (See Section 9.7 for management of treatment-related enterocolitis) 
All patients who experience diarrhea should be advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. 
NOTE: Loperamide/diphenoxylate/atropines should NOT be used for diarrhea symptoms 
unless: (1) it is believed that pembrolizumab-related enterocolitis is unlikely to be present 
after detailed evaluation by gastroenterology, including endoscopy; PLUS (2) approval is 
documented by a gastroenterology specialist. 
9.7 
Immunotherapy-related toxicities 


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Patients should be monitored for signs and symptoms of immunotherapy-related 
toxicities, which include but are not limited to the following: 
• 
Pneumonitis 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
• 
Diarrhea/colitis 
Patients should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). 
o All patients who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high 
dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis [DKA]) 
or ≥Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
For T1DM or Grade 3-4 Hyperglycemia: 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
o Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
• 
Hypophysitis 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid dose 
is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
• 
Hyperthyroidism or hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 


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 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
• 
Hepatic 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
• 
Renal failure or nephritis 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  
9.8 
Management of treatment related enterocolitis 
In patients with severe enterocolitis, pembrolizumab will be held and treatment with 
systemic corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day of prednisone or 
equivalent. When symptoms improve to Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month.  
In patients with moderate enterocolitis, pembrolizumab should be withheld and 
antidiarrheal treatment should be started. If symptoms are persistent for more than one 
week, systemic corticosteroids should be initiated (e.g., 0.5 mg/kg/day of prednisone or 
equivalent). When symptoms improve to Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month. 
9.9a 
Concomitant Medications/Vaccinations (Allowed & Prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial. If there is a clinical indication for any medication or 
vaccination specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the patient’s primary physician. 
9.9a1 
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 in the case report forms (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. 


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Concomitant medications administered 30 days after the last dose of trial 
treatment should be recorded for SAEs and ECIs as defined in Section 10. 
9.9a2 
Prohibited Concomitant Medications 
The following medications are not permitted during the screening and treatment 
phase (including retreatment for post-complete response relapse) of this trial: 
• 
Anti-neoplastic systemic cytotoxic chemotherapy or biological therapy 
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and 
while participating in the trial. Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, varicella/zoster, yellow 
fever, intranasal influenza, rabies, BCG, and typhoid vaccine. 
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology. The use 
of physiologic doses of corticosteroids may be approved after consultation 
with the principal investigator. 
NOTE: Use of steroids during chemoradiation for controlling chemotherapy-
associated nausea and docetaxel associated edema is allowed.  
Patients 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. Patients may receive other medications that the investigator deems to be 
medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this 
trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
9.9b 
Infusion Reaction 
Table 9.9b 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 
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). 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
stopping treatment 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. 
Patients who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
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 study treatment administration. 
9.9c 
Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not 
known if pembrolizumab has transient adverse effects on the composition of sperm. 
For this trial, male patients will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition). 
Female patients will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 


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absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male patients of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and for 120 
days after the last dose of study drug by complying with one of the following: 
(1) practice abstinence† from heterosexual activity; 
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for patients participating at 
sites in this country/region. 
Patients should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to 
participate in the study patients of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study medication initiation (or 14 days 
prior to the initiation of study medication for oral contraception) throughout the study 
period up to 120 days after the last dose of trial therapy. If there is any question that a 
patient of childbearing potential will not reliably comply with the requirements for 
contraception, that patient should not be entered into the study. 


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9.9d 
Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with pembrolizumab, the 
patient will immediately be removed from the study. The site will contact the patient at 
least monthly and document the patient’s status until the pregnancy has been completed 
or terminated. The outcome of the pregnancy will be reported to Mayo Clinic and to 
Merck without delay and within 24 hours to Mayo Clinic and within 2 working days to 
Merck if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the fetus or newborn. If a male subject 
impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to Mayo Clinic and to Merck and followed as 
described above. 
9.9e 
Use in Nursing Adults 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, patients who are breast-feeding are not eligible for 
enrollment. Specific additional information follows for individual agents used in this 
trial. 
9.9e1 
Pembrolizumab 
It is unknown whether pembrolizumab is excreted in human milk. 
9.9e2 
Docetaxel and Doxorubicin 
Doxorubicin has been reported to be found in human milk; patients receiving 
doxorubicin injection should not breast-feed. It is unknown if docetaxel is 
excreted inhuman milk, it is recommended that breast feeding be discontinued. 
 
 


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10.0 
Adverse Event (AE) Monitoring and Reporting  
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
http://ctep.cancer.gov/protocolDevelopment/electronic a
pplications/docs/PregnancyReportFormUpdated.pdf 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=
MC4158-56/Processes/MC4158-56-Process.MC4158-
56  
AND attach 
MedWatch 3500A: 
http://www.fda.gov/downloads/AboutFDA/ReportsMa
nualsForms/Forms/UCM048334.pdf 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo
.edu 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
 
 


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Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application (including 
a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects 
10.1 
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) 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 


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NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) 
on the SAME (Combination) Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions.  
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent require 
an expedited report, unless hospitalization is required. Refer to Section 10.4 for 
specific AE reporting requirements or exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is 
required. 
• An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site. A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from a 
drug overdose. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch 
3500A for Health Professionals (complete all three pages of the form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
or 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/ListFormsAlphabe
tically/default.htm 
Instructions for completing the MedWatch 3500A: 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadFor
ms/UCM387002.pdf 
 
 


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10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
CTCAE System 
Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which 
the event will not be 
expeditedly reported1 
General disorders 
and administrations 
site conditions 
Fatigue  
Grade 3 
 
 
Gastrointestinal 
Vomiting 
Grade 3 
Nausea 
Grade 3 
Oral mucositis 
Grade 3  
Investigations 
Neutrophil count decreased 
≤Grade 4 
White blood cell count 
decreased 
≤Grade 4 
Platelet count decreased 
≤Grade 4 
Weight loss 
Grade 3  
Injury, poisoning, 
and procedural 
complications 
Radiation dermatitis 
Grade 3 
Blood and 
lymphatic system 
disorders 
Anemia 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in 
hospitalization. If the adverse event results in hospitalization, then the standard 
expedited adverse events reporting requirements must be followed.  
Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the hospitalization 
has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for administration of study 
drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in place 
before study entry 
● Hospitalization or other serious outcomes for signs and symptoms of progression of the cancer. 




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10.42 General reporting instructions 
The Mayo IND Coordinator will assist the sponsor-investigator in the processing 
of expedited adverse events and forwarding of suspected unexpected serious 
adverse reactions (SUSARs) to the FDA and IRB. 
Submit form MedWatch 3500A to the FDA, 
 
 or online at 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm. 
Use Mayo Expedited Event Report form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158-
56/Processes/MC4158-56-Process.MC4158-56 for investigational agents or 
commercial/investigational agents on the same arm and attach MedWatch 
3500A. 
Submit to Merck Global Safety (Attn: Worldwide Product Safety Fax
 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 




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o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/Pregna
ncyReportFormUpdated.pdf 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 


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Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation.  
Grading is per CTCAE v4.0 unless alternate grading is indicated in the table 
below: 
CTCAE  
SYSTEM ORGAN 
CLASS 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Blood and lymphatic 
system disorders 
Febrile neutropenia 
 
X 
Gastrointestinal 
Disorders 
Nausea 
X 
X 
Vomiting 
X 
X 
# of Stools 
X 
 
Diarrhea 
 
X 
Mucositis oral 
 
X 
General disorders and 
administration site 
conditions 
Fatigue  
X 
X 
Infections and 
infestations 
Sepsis 
 
X 
Investigations 
Creatinine increased 
X 
X 
 
Neutrophil count decreased 
X 
X 
 
Platelet count decreased 
X 
X 
Nervous system  
Peripheral sensory neuropathy  
X 
X 
Disorders 
Peripheral motor neuropathy  
X 
X 
Skin and subcutaneous 
tissue disorders 
Rash, maculo-papular 
X 
X 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 


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10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
Merck Additional Event Reporting Instructions 
10.81 Events of Clinical Interest (ECIs) 
ECIs are selected non-serious and serious adverse experiences that must be 
reported within 24 hours to Mayo Clinic via email and 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 
subject must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety if it causes the subject 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 subject 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 24 hours to the Sponsor and within 24 hours to Merck Global 
Safety. 
Events of clinical interest for this trial include: 
1. An overdose of Merck product, as defined in Section 10.82, 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. 
10.82 Reporting of Overdose of Pembrolizumab 
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 


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information is available on the treatment of overdose of pembrolizumab. 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 (pembrolizumab), 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 (pembrolizumab) 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 Mayo Clinic 
and within 
2 working days hours to Merck Global Safety. (Attn: Worldwide Product Safety; 
 
10.83 Additional Instructions for AE Reporting to Merck 
A serious adverse event is any adverse event occurring at any dose or during any 
use of Merck’s product 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 another important medical event  
• 
Note: In addition to the above criteria, adverse events meeting either of the 
below criteria, although not serious per ICH definition, are reportable to the 
Merck in the same timeframe as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by Merck for collection 
purposes. 
● Is a new cancer (that is not a condition of the study); 
● Is associated with an overdose. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, 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 must be reported within 24 hours to 
the Sponsor (Mayo Clinic) and within 2 working days to Merck Global Safety if 
it causes the subject 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 subject initiates new anticancer therapy, whichever is earlier, 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 whether or not 
related to the Merck product, must be reported within 24 hours to the Sponsor 
and within 2 working days to Merck Global Safety. 
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 following consent through the end of the specified 


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safety follow-up period specified in the paragraph above, or at any time outside 
of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck Global Safety. 
All patients with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number:  
 
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. 
 
 
 


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11.0 
Treatment Evaluation Using RECIST Guidelines 
NOTE: This study uses RECIST v1.1 template dated 2/16/2011. See the footnote for the table 
regarding measureable disease in Section 11.44, as it pertains to data collection and analysis. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1)(Eisenhauer, Therasse et al. 2009) . Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the short axis measurements in the case of lymph nodes 
are used in the RECIST guideline. 
NOTE: The primary mass and irradiated lymph nodes in neck and upper mediastinum will 
be non-measurable. 
11.1 
Schedule of Evaluations 
Screening (before surgery or chemoradiation): Baseline scan to assess the disease 
status should have been performed within 14 days prior to registration. An FDG PET-CT, 
or CT scan of neck, chest and abdomen and pelvis should be obtained. MRI of the neck is 
acceptable in lieu of CT-neck but not preferred.  
Post-chemoradiation: The first scan after treatment initiation will be performed at the 
completion of chemoradiation. During protocol treatment scans should be performed 
every 9 weeks and then every 3 months in the observation period. Additional scans could 
be obtained at the discretion of the physician.  
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.21  Measurable Disease 
11.211 A non-nodal lesion is considered measurable if its longest diameter can 
be accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with 
CT scan, CT component of a PET/CT, or MRI.  
11.212 A superficial non-nodal lesion is measurable if its longest diameter is 
≥1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or 
imaging. In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is 
recommended. 
11.213 A malignant lymph node is considered measurable if its short axis is 
>1.5 cm when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  
11.22 Non-Measurable Disease 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to 
<1.5 cm). Bone lesions, leptomeningeal disease, ascites, pleural/ 
pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable as well. 
Note: ‘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 patient, these are preferred 
for selection as target lesions. In addition, lymph nodes that have a short axis 


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<1.0 cm are considered non- pathological (i.e., normal) and should not be 
recorded or followed. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 Measurement Methods: 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. For patients having only lesions measuring at least 1 cm to less 
than 2 cm must use CT imaging for both pre- and post-treatment tumor 
assessments. 
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
11.32 Acceptable Modalities for Measurable Disease: 
Conventional CT and MRI: This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. If 
CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  
• 
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. The lesions should be measured on the same pulse 
sequence. 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. 
• 
PET-CT: CT portion of the PET-CT can be used for RECIST measurements 
and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  
• 
FDG-PET: FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' 
disease. A ‘positive’ FDG-PET scanned lesion is defined as one which is 
FDG avid with an update greater than twice that of the surrounding tissue on 
the attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’ New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is 
a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  
ii. If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT at the same evaluation, additional follow-up CT 
scans (i.e., additional follow-up scans at least 4 weeks later) are 
needed to determine if there is truly progression occurring at that 


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site. In this situation, the date of PD will be the date of the initial 
abnormal FDG-PET scan.  
iii If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, it is not classified as PD. 
11.33 Measurement at Follow-up Evaluation:  
• 
Residual disease after chemoradiation is defined as persistent primary 
tumor mass (FDG-avid or nonavid) or any known distant metastatic 
disease as in AJCC stage IVC. 
• 
A subsequent scan must be obtained at least 4 weeks following initial 
documentation of an objective status of either complete response (CR) or 
partial response (PR).  
• 
In the case of stable disease (SD), follow-up measurements must have met 
the SD criteria at least once after study entry at a minimum interval of 8 
weeks (see Section 11.44). 
• 
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. 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in ATC after chemoradiation can 
represent fibrotic tissue) 
11.4 
Measurement of Effect 
11.41 Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline. These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.  
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.  
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD). The 
BSD will be used as reference to further characterize any objective tumor 
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• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target 
lymph nodes will be calculated and reported as the post-baseline sum of 
dimensions (PBSD). If the radiologist is able to provide an actual measure 
for the target lesion (or target lymph node), that should be recorded, even if it 
is below 0.5 cm. If the target lesion (or target lymph node) is believed to be 
present and is faintly seen but too small to measure, a default value of 0.5 cm 
should be assigned. If it is the opinion of the radiologist that the target lesion 
or target lymph node has likely disappeared, the measurement should be 
recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at  
baseline. These lesions and lymph nodes should be followed in accord with 
11.433. 
11.43 Response Criteria 
11.431 
All target lesions and target lymph nodes followed by CT/MRI/PET-
CT/ must be measured on re-evaluation at evaluation times specified in 
Section 11.1. Specifically, a change in objective status to either a PR or 
CR cannot be done without re-measuring target lesions and target 
lymph nodes.  
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response.  
11.432 
Evaluation of Target Lesions 
Complete Response (CR):All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to 
<1.0 cm. 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis 
of all the target lymph nodes at current evaluation) taking as 
reference the BSD (see Section 11.41). 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (<1.0 cm short axis) and 
increased to ≥1.0 cm short axis during follow-up.  
b. At least a 20% increase in PBSD (sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the 
target lymph nodes at current evaluation) taking as reference the 
MSD (Section 11.41). In addition, the PBSD must also 
demonstrate an absolute increase of at least 0.5 cm from the 
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c. See Section 11.32 for details in regards to the requirements for 
PD via FDG-PET imaging. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
11.433 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
Complete Response (CR): 
All of the following must be true: 
a. Disappearance of all non-target 
lesions. 
b. Each non-target lymph node must 
have a reduction in short axis to 
<1.0 cm. 
Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
Progression (PD): 
At least one of the following must be 
true: 
a. At least one new malignant lesion, 
which also includes any lymph node 
that was normal at baseline (<1.0 cm 
short axis) and increased to ≥1.0 cm 
short axis during follow-up.  
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes. (NOTE: Unequivocal 
progression should not normally 
trump target lesion and target lymph 
node status. It must be representative 
of overall disease status change.)  
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
 
 




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document the objective progression even after discontinuation of treatment due to 
symptomatic deterioration. 
 
11.5 
Treatment Evaluation after Completion of Surgery and Post-operative Chemoradiation 
(Cohort A patients)  
11.51 Definition of Recurrence 
The term “recurrence” is used if cancer returns either in the locoregional area of 
the primary tumor or at distant sites following R0 or R1 resection  
11.52 How Recurrence is Determined 
Recurrence is determined radiographically and biopsy could be performed at the 
discretion of treating physician except as detailed below or when CT findings are 
equivocal in the determination of the enrolling physician.  
Locoregional recurrence: Identified by a new soft-tissue mass in the operated 
thyroid bed or regional cervical lymph nodes.  In some cases post-radiation 
changes may make it difficult to distinguish from early tumor progression. In 
cases in which the diagnosis is ambiguous, discussion with the PI should occur. 
Performance of tissue biopsy should be considered prior to assigning a diagnosis 
of locoregional recurrent disease.  
 
12.0 
Descriptive Factors  
12.1 
Associated lympocytic/autoimmune thyroiditis: Yes vs. no 
12.2 
Coexistent differentiated thyroid cancer: Yes vs. no 
12.3 
Primary tumor resected: Yes vs. no 
12.4 
Prior TKI use:Yes vs. no 
12.5 
Prior/remote/unrelated neck radiotherapy (therapeutic, not diagnostic): Yes vs. no 
12.6 
Prior history of differentiated thyroid cancer: Yes vs. no 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Continuation of treatment 
Patients who have not had disease progression and have experienced acceptable toxicity 
are to continue treatment per protocol until confirmed PD, unacceptable toxicity or 
refusal. Patients with PD will proceed to EM and others will proceed to observation until 
PD. 
13.2 
Progressive disease (PD) 
If radiologic imaging verifies initial disease progression per RECIST 1.1 or 
recurrence after surgery, treatment may continue at the discretion of the 
Investigator until repeat imaging ≥6 weeks later. The Investigator’s decision to 
continue treatment while awaiting repeat imaging should be based on the subject’s 
overall clinical condition guided by the following criteria: 
• 
Absence of signs and symptoms indicating disease progression 
• 
No significant decline in ECOG performance status 
• 
Absence of rapid progression of disease 


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• 
Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
If repeat imaging confirms disease progression due to any of the scenarios listed below, 
patients will be discontinued from study therapy. 
• 
Non-target disease resulting in initial disease progression is worse (qualitative) 
• 
New lesion resulting in initial disease progression is worse (qualitative) 
• 
Additional new lesion(s) since last evaluation 
In determining whether or not the tumor burden has increased or decreased, Investigators 
should consider all target lesions as well as non-target lesions. When feasible, study 
treatment should not be discontinued until progression is confirmed.  
If the initial documented progression is confirmed, patients will go to the event-
monitoring phase until death or a maximum of 5 years post-registration. 
13.3 
Off protocol treatment for reasons other than PD 
Patients who go off protocol treatment for reasons other than PD will go to the 
observation phase for 1 year and then to EM. 
13.4 
Observation 
If the patient has achieved CR, PR, or SD, the patient will continue treatment per protocol 
and then observed every 3 months for 1 year. 
13.5 
Duration of therapy for CR 
Patients who achieve a CR will complete therapy per protocol. After that, they should be 
observed (see 13.4 above) every 3 months for 1 year and proceed to event monitoring. If 
they develop PD during observation, then they will proceed to event monitoring. 
13.6 
Duration of therapy for PR or SD 
Patients who are in PR or SD will continue on therapy per protocol. Subsequent treatment 
is at the discretion of their attending physician 
13.7 
CNS PD  
Patients who develop PD in the CNS may receive whole brain radiotherapy (WBRT) or 
gamma-knife radiotherapy and will be considered to have PD and proceed to EM. 
13.8 
Non-CNS PD  
Patients who develop non-CNS PD at any time should go to event monitoring. 
These patients should be treated with alternative chemotherapy if their clinical 
status is good enough to allow further therapy.  
13.9b Definition of Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol.  


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13.9c 
Definition of Major Violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 18.0 of the protocol. 
13.9d Definition of Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 




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14.2 
Collection, Processing and Shipping  
14.21  No kits are required for this study. (Mayo Clinic in Rochester will use Special 
Study cards in place of kits) 
14.22  MCR samples can be collected Monday-Friday. 
14.23  Label specimen tube(s) with protocol number, patient study ID number, and time 
and date blood is drawn. 
14.24  Collect and process all blood/blood products according to the protocol. 
14.25  Shipping (MCA/MCF only) - NA  
14.3 
Other body fluids handling - None 
14.4 
Background and Methodology 
Blood/blood product samples will be collected for the following research:  
14.41  Blood for correlative research (
). One 6 ml EDTA tube whole blood and 
one red 10 ml serum tube specimen should be collected per table 14.1 for 
analysis of circulating MDSCs and other circulating immune markers. These 
samples will be collected at baseline and after chemoradiation per table 14.1.This 
specimen will only be collected at Mayo Rochester; other site(s) will not 
participate in this portion of the translational study. Whole blood should be sent 
to the Dietz Lab, where processing will be completed. 
14.43  Blood for correlative research (
).  One 10 mL whole blood sample 
will be collected in AccuCyte Blood Collection Tubes, which contain the 
proprietary RareCyte cell preservative. These will be collected at baseline, during 
and after chemoradiation per table 14.1. These samples will be shipped or 
delivered immediately at ambient temperature to Mayo Clinic Rochester and then 
processed through the RareCyte system within three days of collection. CTCs 
will be captured onto glass slides (8 slides per blood sample) for subsequent 
immunofluorescent staining, selection, and single cell isolation.  
Specimens will be collected at the following time points:  
• Baseline   
• Prior to starting third cycle of pembrolizumab (Cycle 3, Day 1 ±3 days)  
• Following completion of chemoradiation therapy preferably before next dose of 
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15.0 
Drug Information 
15.1 
Pembrolizumab (MK-3475, SCH 900475, Keytruda®) 
15.11 Background 
Pembrolizumab is a potent humanized IgG4 monoclonal antibody with high 
specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
PD-L1 and PD-L2. Based on preclinical in vitro data, pembrolizumab has high 
affinity and potent receptor blocking activity for PD-1. 
15.12 Formulation  
Pembrolizumab is available as a liquid 25 mg/mL, 100 mg/vial.  
15.13 Preparation and storage 
Vials should be stored in the refrigerator at temperatures between 2-8°C.  
Drug concentrate is further diluted with normal saline (or 5% dextrose in the 
concentration range of 1 to 10 mg/mL) in IV containers made of polyvinyl 
chloride (PVC) or non-PVC material. The infusion solution in the IV bag should 
be immediately administered. Pembrolizumab solutions may be stored at room 
temperature for a cumulative period of up to 4 hours. This includes room 
temperature storage of reconstituted solution in vials, room temperature storage 
of infusion solution in the IV bag and the duration of infusion. 
In addition, IV bags may be stored 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. 
15.14 Administration 
Pembrolizumab is administered by intravenous infusion over 30 minutes via a 
0.22 micron in-line filter. The final infusion volume must be between 1 and 10 
mg/mL. Maximum rate of infusion should not exceed 6.7 mL/minute through a 
peripheral or indwelling catheter. Flush the line with 0.9% NaCL following the 
completion of the infusion. 
15.15 Pharmacokinetic information 
a) Absorption – Steady state is predicted to be acheived after ~18 weeks of 
repeated dosing, with ~2.2-fold accumulation in exposure during administration 
Q3W relative to exposure observed following singl dose administration. The 
majority (~81%) of this accumulation has occurred by the fourth dose. In the 
dose rane studied for efficacy (2 to 10 mg/kg), pembrolizumab exposure 
increases in a dose-proportional manner, with clearance being independent of 
time or pembrolizumab concentration. 
b) Distribution – Pembrolizumab has a limited volume of distribution.  
c) Excretion – The systemic clearance of pembrolizumab is ~0.22 L/day and the 
terminal elimination half-life (t½) is estimated to be ~26 days. 
d) Metabolism – Pembrolizumab is catabolized by the general protein 
degradation processes; typical small molecule metabolic pthways (e.g., 
cytochrome P450 enzymes, clucuronosyltransfersases) do not contribute to its 
clearance. 
15.16 Potential Drug Interactions 
There are no known significant drug interactions. 


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15.17 Known potential toxicities 
Common known potential toxicities, >10%: 
Dermatologic: Pruritus, skin rash 
Gastrointestinal:diarrhea 
Neuromuscular & skeletal: Arthralgia, back pain 
Respiratory: Cough 
Less common known potential toxicities, 1% - 10%: 
Infustion related reactions 
Dermatologic: vitiligo, severe skin reactions 
Endocrine & metabolic: Hypothyroidism, hyperthyroidism, hyponatremia 
Gastrointestinal: Colitis, abdominal pain 
Respiratory:  Pneumonitis 
Rare known potential toxicities, <1% (Limited to important or life-
threatening): 
Secondary adrenocortical insufficiency (immune-mediated), hepatitis (including 
autoimmune hepatitis), hypophysitis, nephritis, Guillain-Barre syndrome 
(immune-mediated), myositis (immune-mediated), pancreatitis (immune-
mediated), uveitis (immune-mediated), and Type I diabetes mellitus. 
Two important potential risks have been identified, although the data available 
thus far for these events does not provide sufficient evidence of a causal 
relationship to pembrolizumab. The two important potential risks are: a) 
myasthenic syndrome, and b) an increased risk of severe complications (such as 
early severe graft versus host disease and venoocclusive disease) of allogeneic 
transplant in patients with hematologic malignancies who have previously been 
treated with PD-1 inhibitors. The Sponsor continues to monitor and collect data 
on these potential risks in order to further characterize their potential relationship 
to pembrolizumab.  
Two important updates from additional information from the clinical trial and 
post-marketing environments include:  a) A new important risk of myocarditis.  
Cases with fatal outcome have been reported. b) Further characterization of the 
existing important identified risk of severe skin reactions to include cases of 
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some 
with fatal outcome. 
15.18 Drug procurement 
Pembrolizumab will be provided free of charge to study participants by Merck. 
15.19 Nursing Guidelines 
15.191 
Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team 
immediately. Side effects may be immediate or delayed up to months 
after discontinuation of therapy. Most side effects are reversible with 
prompt intervention of corticosteroids. 
15.192 
Diarrhea can be seen however, is less common than that seen with anti-
CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 


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stools and/or change in baseline, blood in the stool, abdominal pain to 
the study team immediately.  
15.193 
Rash/pruritis/dermatitis is seen. Patients should report any rash to the 
study team. Treat per Section 9.0 and monitor for effectiveness.  
15.194 
Monitor LFTs closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team 
immediately. 
15.195 
Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, 
cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
15.196 
Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysitis, and adrenal insufficiency) are seen with this agent. 
Patients may present only with the vague sense of fatigue and “not 
feeling well.” Additional symptoms may be that of nausea, sweating 
and decreased activity tolerance. Instruct patients to report these signs 
or symptoms immediately and obtain appropriate labs as ordered by 
MD. 
15.197 
Patients who are started on steroid therapy for any side effects of 
pembrolizumab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and 
be severe. Patients may be on steroid therapy for weeks. Instruct 
patients to report any increase or change in side effects with any 
dosage decrease as patients may need a slower taper.  
15.198 
Fatigue is common and may or may not be associated with immune 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 
15.199a Patients should avoid receiving live vaccines within 30 days of study 
drug administration or per other study guidelines.  
15.199b Patients who have undergone an allogenic bone marrow transplant, 
have an increased risk of severe complications including early GVHD, 
and venoocclusive disease, if they have previously been treated with 
pembrolizumab 
15.199c Myocarditis has been reported and associated with pembrolizumab. 
Instruct patients to report chest pain, SOB, or dyspnea to study team 
immediately and/or seek emergency medical attention. 
 
 


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15.2 
Doxorubicin 
15.21 Background: 
Doxorubicin inhibits DNA and RNA synthesis by intercalation between DNA 
base pairs by inhibition of topoisomerase II and be steric obstruction. 
Doxorubicin intercalates at points of local uncoiling of the double helix. 
Although the exact mechanism is unclear, it appears that direct binding to DNA 
(intercalation) and inhibition of DNA repair (topoisomerase II inhibition) result 
in blockade of DNA and RNA synthesis and fragmentation of DNA. Doxorubicin 
is also a powerful iron chelator; the iron-doxorubicin complex can bind DNA and 
cell membranes and produce free radicals that immediately cleave the DNA and 
cell membranes. 
15.22 Formulation:  
Commercially available for injection as:  
Injection, powder for reconstitution: 10 mg, 50 mg 
Injection, solution: 2 mg/mL (5 mL, 10 mL, 25 mL, 100 mL) 
15.23 Preparation, storage, and stability:  
Refer to package insert for complete preparation and dispensing instructions. 
Store intact vials of solution under refrigeration and protect from light; store 
intact vials of lyophilized powder at room temperature. Reconstitute lyophilized 
powder with NS to a final concentration of 2 mg/mL. Reconstituted vials are 
stable for 7 days at room temperature and 15 days under refrigeration when 
protected from light. Infusions are stable for 48 hours at room temperature when 
protected from light. Solutions diluted in 50-1000 mL D5W or NS are stable for 
48 hours at room temperature when protected from light. Stable with vincristine 
in NS for five days at room temperature protected from light. 
15.24 Administration 
Refer to the treatment section for specific administration instructions. 
Doxorubicin is administered I.V. push over at least 3-5 minutes, IVPB over 15-
60 minutes, or continuous infusion. Avoid extravasation. Flush with 5-10 mL of 
I.V. solution before and after drug administration. Incompatible with heparin. 
15.25 Pharmacokinetic information: 
Distribution: Vd: 809-1214 L/m2; to many body tissues, particularly liver, 
spleen, kidney, lung, heart; does not distribute into the CNS; crosses placenta 
Protein binding, plasma: 70% to 76% 
Metabolism: Primarily hepatic to doxorubicinol (active), then to inactive 
aglycones, conjugated sulfates, and glucuronides 
Half-life elimination:  
Distribution: 5-10 minutes 
Elimination: Doxorubicin: 1-3 hours; Metabolites: 3-3.5 hours 
Terminal: 17-48 hours 
Male: 54 hours; Female: 35 hours 
Excretion: Feces (~40% to 50% as unchanged drug); urine (~5% to 12% as 
unchanged drug and metabolites) 
Clearance: Male: 113 L/hour; Female: 44 L/hour 
 
 


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15.26 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP2D6 (major), 3A4 (major); Inhibits 
CYP2B6 (moderate), 2D6 (weak), 3A4 (weak)  
Increased Effect/Toxicity: Bevacizumab, trastuzumab, and cyclophosphamide 
may enhance the cardiotoxic effect of doxorubicin. Docetaxel and paclitaxel may 
enhance the adverse/toxic effect of doxorubicin; may increase the serum 
concentration of doxorubicin and may also increase the formation of toxic 
doxorubicin metabolites in heart tissue. Cyclosporine and sorafenib may increase 
the levels/effects of doxorubicin. CYP2D6 inhibitors may increase the 
levels/effects of doxorubicin. CYP3A4 inhibitors may increase the levels/effects 
of doxorubicin. Doxorubicin may increase the levels/effects of CYP2B6 
substrates. 
Decreased Effect: Digoxin may diminish the cardiotoxic effect of doxorubicin. 
Doxorubicin may decrease the absorption and serum concentration of cardiac 
glycosides. CYP3A4 inducers may decrease the levels/effects of doxorubicin. 
Herb/Nutraceutical Interactions: Avoid St. John’s wort (may decrease 
doxorubicin levels). Avoid black cohosh, dong quai in estrogen-dependent 
tumors.  
15.27 Known potential adverse events 
Consult the package insert for the most current and complete information.  
Common known potential toxicities, >10%: 
Dermatologic: Alopecia 
Gastrointestinal: Mucositis, nausea, vomiting  
Genitourinary: Discoloration of urine  
Hematologic: Leukopenia/neutropenia (75%; nadir: 10-14 days; recovery: by 
Day 21); thrombocytopenia and anemia  
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Congestive heart failure 
Central nervous system: Malaise 
Dermatologic: Itching, rash, discoloration of saliva, sweat, or tears, radiation 
recall 
Endocrine & metabolic: Amenorrhea, dehydration, infertility (may be 
temporary), hyperuricemia  
Gastrointestinal: Abdominal pain, anorexia, diarrhea, GI ulceration, colon 
necrosis  
Local: Skin “flare” at injection site, urticaria  
Neuromuscular & skeletal: Weakness 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Dermatologic: Photosensitivity, ulceration or severe reaction at the injection site 
if extravasation occurs. 
15.28 Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal 
commercial supply chain or wholesaler. 
 
 


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15.29 Nursing Guidelines:  
15.291 
Check CBC and platelet counts.  Instruct patient to watch for signs of 
infection, bleeding, and anemia. 
15.292 
Advise patient that their urine may turn pink in color for approximately 
24 hours after administration of the drug. 
15.293 
Adriamycin is a vesicant.  Check IV patency before and frequently 
during administration.  If extravasation occurs, refer to institutional 
guidelines. 
15.294 
Hair loss occurs 2-4 weeks after initial injection and can be complete. 
Regrowth begins 2-3 months after discontinuation. 
15.295 
Beware of Adria “flare” that can occur during administration.  The 
reaction consists of an erythematous streak up the vein receiving the 
infusion.  Adjacent veins may also demonstrate red streaks.  Urticaria 
and pruritus can be associated with the reaction.  The use of 
corticosteroids and/or antihistamines has been helpful. 
15.296 
Administer antiemetics to minimize nausea and vomiting. 
15.297 
Assess for alterations in mucous membranes. Stomatitis occurs within 
7-10 days after injection.  It begins with burning sensation and can 
progress to ulceration, which can last 3 days. Carafate slurry may be 
useful. Adequate nutritional counseling is important. Topical 
anesthetics such as viscous Xylocaine can be used symptomatically. 
15.298 
Advise patient that there is often significant malaise and fatigue  
1-2 weeks after injection. 
15.299a Adriamycin may potentiate toxicity of other antineoplastic therapies. It 
has reportedly exacerbated Cyclophosphamide (Cytoxan, CTX) 
induced hemorrhagic cystitis. 
15.299b Assess heart and lung sounds.  Monitor vital signs (resting pulse). Be 
alerts to early signs of cardiotoxicity, i.e., dyspnea, steady weight gain, 
nonproductive cough, arrhythmias, tachycardia, and pulmonary rales. 
Instruct patients to report any of these signs or symptoms to their 
health care provider. 
15.299c Document cumulative dose, which should not exceed maximum 
cumulative dose. 
15.299d Advise patient of probable facial flushing for several hours after drug 
administration, especially if given quickly. 
 
 


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15.3 
Docetaxel (Taxotere®, TATER)  
15.31 Background 
Antineoplastic Agent, Antimicrotubular, Taxane derivative. Docetaxel promotes 
the assembly of microtubules from tubulin dimers, and inhibits the 
depolymerization of tubulin which stabilizes microtubules in the cell. This results 
in inhibition of DNA, RNA, and protein synthesis. Most activity occurs during 
the M phase of the cell cycle. 
15.32 Formulation 
Note: Docetaxel is now available as a one-vial formulation in two 
concentrations: 10 mg/mL and 20 mg/mL. The older formulation included 2 vials 
which consisted of a concentrated docetaxel vial and a diluent vial, resulting in a 
reconstituted concentration of 10 mg/mL. Admixture errors could occur due to 
the concentration difference between the new formulations of 10 mg/mL and 20 
mg/mL and the old formulation (10 mg/mL). Do not use the two-vial formulation 
with the one-vial formulation for the same admixture product. 
15.33 Preparation, storage, and stability 
Storage conditions: Store the packaged docetaxel between 2 and 25°C (36 and 
77°F). Retain in the original package to protect from bright light. Freezing does 
not adversely affect the product. 
One-vial formulation: Note: One-vial formulation is available in two 
concentrations: 10 mg/mL and 20 mg/mL. Further reconstitution with diluent is 
not required. Further dilute for infusion in 250-500 mL of NS or D5W in a non-
DEHP container (e.g., glass, polypropylene, polyolefin) to a final concentration 
of 0.3-0.74 mg/mL. Gently rotate to mix thoroughly. Solutions prepared from the 
one-vial formulation and diluted for infusion should be used within 4 hours of 
preparation (infusion should be completed within 4 hours). 
15.34 Administration 
Administer IV infusion over 1-hour through nonsorbing polyethylene lined (non-
DEHP) tubing; in-line filter is not necessary. Note: Premedication with 
dexamethasone 8 – 10 mg orally twice daily for 3-5 days, beginning the day 
before docetaxel administration is recommended to decrease the incidence and 
severity of fluid retention and prevent hypersensitivity reactions and 
pulmonary/peripheral edema. When administered as sequential infusions, taxane 
derivatives should be administered before platinum derivatives (cisplatin, 
carboplatin) to limit myelosuppression and to enhance efficacy. Infusion should 
be completed within 4 hours of final preparation. 
15.35 Pharmacokinetic information 
Docetaxel exhibits linear pharmacokinetics at the recommended dosage range. 
Distribution: Extensive extravascular distribution and/or tissue binding; Vd: 80-
90 L/m2, Vdss: 113 L (mean steady state) 
Protein binding: ~94% to 97% 
Metabolism: Hepatic; oxidation via CYP3A4 to metabolites 
Half-life elimination: Terminal: ~11 hours 
Excretion: Feces (~75%, <8% as unchanged drug); Urine (~6%)  
 
 


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15.36 Potential Drug Interactions 
Cytochrome P450 Effect: Substrate (major) of CYP3A4; Inhibits CYP3A4 
(weak).  
Increased Effect/Toxicity: CYP3A4 inhibitors may increase the levels/effects of 
docetaxel. Concomitant use of docetaxel with a potent CYP3A4 inhibitor should 
be avoided. If systemic administration of a potent CYP3A4 inhibitor cannot be 
avoided, a 50% reduction in docetaxel dose should be considered along with 
close monitoring for docetaxel toxicity. Refer to the package insert or LexiComp1 
for example inhibitors. When administered as sequential infusions, observational 
studies indicate a potential for increased toxicity when platinum derivatives 
(carboplatin, cisplatin) are administered before taxane derivatives (docetaxel, 
paclitaxel). Taxane derivatives may enhance the adverse/toxic effect of 
anthracyclines. 
Decreased Effect: CYP3A4 inducers may decrease the levels/effects of 
paclitaxel. Refer to the package insert or LexiComp1 for example inducers. 
Ethanol/Herb/Nutraceutical Interactions: Avoid ethanol (due to GI irritation). 
Avoid St John’s wort (may decrease docetaxel levels). 
Immunosuppressants: (ex: denosumab, pimecrolimus, tacrolimus, etc.) 
docetaxel may enhance the adverse/toxic effect of immunosuppressants 
(risk for serious infections may increase) 
Myleosuppressived Agents: increased risk of agranulocytosis and/or 
pancytopenia (ex: clozapine, dipyrone) 
BCG:  Immunosuppressants may diminish the therapeutic effect of BCG 
Treatment with Docetaxel Products May Cause Symptoms of Alcohol 
Intoxication June 2014  
The FDA is warning health care providers and patients that docetaxel injection 
products contain ethanol, which may cause patients to experience symptoms of 
alcohol intoxication during and after treatment. The FDA is revising the labels of 
all docetaxel drug products to warn about this risk. Health care providers should 
consider the alcohol content of docetaxel products when prescribing or 
administering the drug to patients, particularly in those whom alcohol intake 
should be avoided or minimized and when using it in conjunction with other 
medications. Patients should avoid driving, operating machinery, or performing 
other activities that are dangerous for one to two hours after docetaxel infusion. 
15.37 Known potential adverse events 
Consult the package insert for the most current and complete information. 
Percentages reported for docetaxel Monotherapy; frequency may vary depending 
on diagnosis, dose, liver function, prior treatment, and premedication. The 
incidence of adverse events was usually higher in patients with elevated liver 
function tests. 
Common known potential toxicities, >10%: 
Cardiovascular: Fluid retention 
Central nervous system: Neurosensory events including neuropathy, fever, 
neuromotor events. 
Dermatologic: Alopecia, cutaneous events, nail disorder 
Gastrointestinal: Stomatitis, diarrhea, nausea, vomiting 
Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia, febrile 
neutropenia 
Hepatic: Transaminases increased 


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Neuromuscular & skeletal: Weakness, myalgia 
Respiratory: Pulmonary events 
Miscellaneous: Infection, hypersensitivity 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Left ventricular ejection fraction decreased, hypotension 
Central nervous system: Peripheral motor neuropathy 
Dermatologic: Rash/erythema 
Gastrointestinal: Taste perversion 
Hepatic: Bilirubin increased, alkaline phosphatase increased 
Local: Infusion-site reactions including hyperpigmentation, inflammation, 
redness, dryness, phlebitis, extravasation, swelling of the vein 
Neuromuscular and skeletal: Arthralgia 
Ocular: Epiphora associated with canalicular stenosis 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Acute myeloid leukemia, acute respiratory distress syndrome, anaphylactic 
shock, angina, ascites, atrial fibrillation, atrial flutter, bleeding episodes, 
bronchospasm, cardiac tamponade, chest pain, chest tightness, colitis, 
conjunctivitis, constipation, cutaneous lupus erythematosus, deep vein 
thrombosis, dehydration, disseminated intravascular coagulation, drug fever, 
duodenal ulcer, Dyspnea, dysrhythmia, ECG abnormalities, erythema 
multiforme, esophagitis, gastrointestinal hemorrhage, gastrointestinal 
obstruction, gastrointestinal perforation, hand and foot syndrome, hearing loss, 
heart failure, hepatitis, hypertension, ileus, intestinal pneumonia, ischemic colitis, 
lacrimal duct obstruction, loss of consciousness (transient), MI, multiorgan 
failure, Myelodysplastic syndrome, neutropenic enterocolitis, ototoxicity, pleural 
effusion, pruritus, pulmonary edema, pulmonary embolism, pulmonary fibrosis, 
radiation pneumonitis, radiation recall, renal insufficiency, seizure, sepsis, sinus 
tachycardia, Stevens-Johnson syndrome, syncope, toxic epidermal necrolysis, 
tachycardia, thrombophlebitis, unstable angina, visual disturbances (transient) 
15.38 Nursing guidelines 
15.381 
Monitor CBC closely, as neutropenia, and thrombocytopenia are 
common and may be life threatening, and dose limiting.  Instruct 
patient to report any signs or symptoms of infection, any unusual 
bruising, or bleeding.  
15.382 
Administer antiemetics as ordered. Evaluate for their effectiveness. 
15.383  
Monitor for signs/symptoms of hypersensitivity reactions that may 
include chills, rigors, dyspnea, bronchospasms, etc.  Stop infusion 
immediately and administer proper emergency treatment. 
15.384 
Because of the risk of anaphylaxis and development of edema, instruct 
patient that is imperative to take steroid premedications as ordered. 
Decrease in steroids has been recommended in this protocol. Please 
follow guidelines as mentioned in Section 9.5. 
15.385 
Instruct patient on proper oral care, as mucositis may occur. 
15.386 
Advise patient about alopecia. 
15.387 
Monitor liver function tests. 


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15.388 
Drug is a vesicant.  Monitor infusion site frequently for signs of 
irritation or infiltration.  Drug extravasation causes acute streaking, 
burning pain, and discoloration at the site.  Skin may be reddened for 
several weeks and occasionally blister and/or peel.  Reactions are 
usually reversible over time.   Because of this central venous access 
may be necessary.  Discuss with MD if patient has poor peripheral 
venous access.  If docetaxel concentrate or diluted solution comes into 
contact with skin, wash with soapy water immediately.  If it comes into 
contact with mucosa, wash with warm water immediately. 
15.389a Instruct patient to report any signs of peripheral neuropathy to the 
health care team (pain, numbness, tingling). 
15.389b Monitor for signs and symptoms of fluid retention, weight gain, ascites 
and CHF. 
15.389c Instruct patient about possible facial flushing, rash, and skin and nail 
changes.  Monitor for signs and symptoms of hand/foot syndrome. 
However premedication with steroids can minimize this side effect.  
Discuss with MD possible ways to manage itching and skin changes 
that may occur up to a week after docetaxel administration.  Advise 
patients that nails may crack, peel, or fall off all together. This may be 
a chronic toxicity.  Instruct patient to keep nails clean, short and to 
avoid wearing nail polish or artificial nails. 
15.189d In case of overdose, patient should be hospitalized and vital signs 
monitored.   
 


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16.0  
Statistical Considerations and Methodology  
16.1 
Statistical Design 
A one stage design with an interim analysis based on the Simon’s optimal design (Simon 
1989) was chosen to demonstrate efficacy of pembrolizumab in improving overall 
survival in combination with standard chemo-radiotherapy in ATC in comparison to 
historical cohort. This design will permit early stopping of the trial if there is strong 
evidence that the study regimen is inactive. 
16.11 Primary endpoint 
The primary endpoint is the 6-month overall survival rate in Cohort A and B 
combined. The 6- month overall survival rate is defined as the total number of 
efficacy evaluable patients who are alive 6 months from registration divided by 
the total number of efficacy evaluable patients enrolled on study. All patients 
meeting the eligibility criteria who have signed a consent form and have begun 
treatment will be evaluable for 6- month overall survival. 
16.12 Operating Characteristics 
ATC has dismal prognosis and has the historical median OS of 6 months 
(Goutsouliak and Hay 2005; Foote, Molina et al. 2011; Sherman, Lim et al. 
2011). It is designed as a one-sided test to detect a ≥48.5% reduction of the 
hazard rate associated with overall survival (OS) when compared to historical 
median OS of 6 months, favoring the addition of pembrolizumab. To evaluate 
ATC, the largest 6-months overall survival rate where the addition of 
pembrolizumab would be considered ineffective in this population is 50%, and 
the smallest that would warrant further subsequent studies is 70%. The study 
design proposed below yields an 80% chance of detecting that the 6-month 
overall survival rate is at least 70% at a one-sided 0.2 significance level. 
We will have two cohorts, Cohort A, for patients who will undergo surgery and 
chemoradiation here at Mayo, and Cohort B, patients in whom surgery is not 
indicated (mostly because of involvement of critical structures in neck). The 
following decision rule is applied to patients in Cohort A and B combined: 
16.121 
Interim Analysis: Enter 10 eligible patients. If more than 6 of the first 
10 evaluable patients enrolled are alive at 6 months then we would 
proceed with accrual. If not, patient accrual will be terminated and the 
regimen would be considered inactive in this patient population 
16.122 
Final Analysis: Enter an additional 10 eligible patients. If at least 12 of 
the total 20 evaluable patients enrolled are alive at 6 months, 
consideration would be given to recommending this treatment for 
further testing in this patient population. If 11 or fewer patients 
enrolled are alive at 6 months, we will consider this regimen 
ineffective in this patient population. 
16.123 
Overaccrual: If more than the target number of patients are accrued, 
the additional patients will not be used to evaluate the stopping rule or 
used in any decision making process.  
16.124 
NOTE: The trial will not be halted while the first 10 patients are 
evaluated for the interim analysis. However, if the accrual is especially 


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rapid, we may temporarily suspend accrual to prevent missing 
important acute toxicity patterns. 
16.13 Power and Significance Level 
Assuming that the number of 6-month survivor is binomially distributed, the 
probability of declaring that this regimen warrants further studies (i.e. statistical 
power) under various tumor response rates and the probability of stopping 
accrual after the first stage can be tabulated as a function of the true tumor 
response rates as shown in the following table. 
If the true 6-month survival rate is 
45% 50% 55% 60% 65% 70% 75% 
Then the probability of declaring that the 
regimen warrants further study is… 
0.10 0.20 0.33 0.50 0.66 0.80 0.91 
And the probability of stopping at the 
completion of stage 1 is… 
0.74 0.62 0.50 0.37 0.25 0.15 0.08 
16.14 Sample Size 
A total of 20 evaluable patients will be accrued in Cohort A and B combined per 
study design, unless the study is permanently closed at interim analysis or undue 
toxicity is observed. We anticipate accruing an additional 5 patients in order to 
account for ineligibility, cancellation, major treatment violation, or other reasons. 
Therefore, maximum accrual is 25 patients for this trial. 
16.15 Accrual Time and Study Duration 
No similar studies have been conducted for comparison. Based on our anecdotal 
experience from referrals of patients from outside institutions who would 
otherwise fit eligibility criteria we believe we will be able to enroll 1 patient per 
month at our institution (Mayo Clinic). We believe we can complete accrual 
within the proposed 2-year period. 
16.2 
Analysis Plan 
16.21 Primary Endpoint 
16.211 
Definition: The primary endpoint of this trial is the overall survival rate 
at 6 months. This is defined as the proportion of evaluable patients who 
are alive at 6 months. We consider a success to be alive. All patients 
meeting the eligibility criteria who have signed a consent form and 
have begun treatment will be considered evaluable. 
16.212 
Estimation: The proportion of successes will be estimated by the 
number of successes divided by the total number of evaluable patients. 
Confidence intervals for the true success proportion will be calculated. 
16.22 Definitions and analyses of secondary clinical endpoint 
Safety and tolerability of pembrolizumab with chemoradiotherapy: All adverse 
events will be graded using the NCI CTCAE Version 4.0. For each type of 
adverse event classified as either possibly, probably, or definitely related to study 
treatment, the proportion of patients experiencing a severe (Grade 3 or higher) 
adverse event will be noted per cycle. The maximum grade for each type of 
adverse event will be recorded for each patient, and frequency tables will be 
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16.23  Exploratory endpoints:  
16.231  
Numbers of patients with locoregional recurrence and locoregional 
progression in the thyroid bed or regional lymph nodes will be 
summaries using descriptive statistics. 
16.232 
Numbers of patients with distant metastasis will be summarized using 
descriptive statistics.  
16.24 Correlative aims:  
16.241 
To evaluate the evolution of the immune profile of circulating immune 
cells in response to therapy in ATC patents, and to assess potential 
correlations with outcomes on an exploratory basis. For the immune 
profile, a plot of the fold change versus response status will be 
constructed to visually assess differences between those whose tumor 
responded to treatment and those whose tumor did not. Wilcoxon rank 
sum tests will be used to examine whether fold changes in a given 
immune profile differs between whose tumor responded to treatment 
and those whose tumor did not. 
16.242 
To determine if pre-therapy circulating tumor cell load might predict 
response and recurrence. Wilcoxon rank sum tests will be used to 
examine whether the pre-therapy circulating tumor cell load differs 
between whose tumor responded to treatment and those whose tumor 
did not, and between those who had recurrence versus who did not.  
16.242 
To evaluate ATC PD-1 and PDL-1 staining in tumor cells and tumor 
stroma as candidate biomarkers for prognostic and/or response in ATC. 
Wilcoxon rank sum tests will be used to examine whether PD-1 and 
PD L-1 staining differs between whose tumor responded to treatment 
and those whose tumor did not. 
16.242 
To examine associations between tumor response and somatic 
mutational status in archived tumors, a 95% confidence interval for the 
difference in proportion of patients who have a documented tumor 
response among those with that particular biomarker present and 
proportion of patients who have a documented tumor response among 
those without that particular biomarker present. 
16.3 
Reporting and Exclusions 
16.31 Evaluation of adverse events.  
All subjects will be evaluable for adverse events from the time of their first 
treatment with pembrolizumab. 
16.32 Evaluation of response.  
All subjects included in the study must be assessed for response to treatment, 
even if there are major protocol treatment deviations or if they are ineligible. 
Each subject will be assigned one of the following categories: 1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early death because 
of other cause, or 9) unknown (not assessable, insufficient data). [Note: By 
arbitrary convention, Category 9 usually designates the “unknown” status of any 
type of data in a clinical database.] 


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All of the subjects who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main analysis 
of the response rate. Subjects in response categories 4-9 should be considered to 
have a treatment failure (disease progression). Thus, an incorrect treatment 
schedule or drug administration does not result in exclusion from the analysis of 
the response rate. Precise definitions for categories 4-9 will be protocol specific.  
All conclusions should be based on all eligible subjects. Subanalyses may then be 
performed on the basis of a subset of subjects, 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 subjects from the analysis 
should be clearly reported. The 95% confidence intervals should also be 
provided. 
16.4 
Monitoring 
The principal investigator and the study statistician will review the study periodically to 
identify accrual, toxicity, and any endpoint problems that might be developing. In 
addition, this study will be monitored according to the Mayo Clinic Cancer Center 
(MCCC) Data Safety Monitoring Plan that is currently in place. The MCCC Data Safety 
Monitoring Board (DSMB) is responsible for reviewing safety data for this trial at least 
twice a year, based on reports provided by the MCCC Statistical Office. 
16.41 Adverse Event Stopping Rules 
NOTE: NCI CTCAE v4.0 will be used to determine grading for adverse event 
stopping rules. The AE stopping rule will be applied to patients in Cohorts A and 
B combined. 
After first five patients are enrolled the enrollment will be suspended until all 
5 patients complete chemoradiation. After the first 5 patients, if we see three or 
more patients develop any immune-related adverse events attributed to the 
study drug (“possible”, “probable” and “definite” only) leading to permanent 
discontinuation of the chemoradiation  then further enrollment will be 
suspended. 
NOTE: Autoimmune thyroiditis is allowed. 
16.5 
Results Reporting on ClinicalTrials.gov 
At study activation, this study will have been registered within the “ClincialTrails.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on www.ClinicalTrials.gov. For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 3 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 6 months. 
16.6 
Subset Analyses for Minorities:  
16.61 Study availability 
This study will be available to all eligible patients, regardless of gender, race or 
ethnic origin.  
 
 


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16.62 Statistical analysis by subset 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analyses will 
look for differences in treatment effect based on racial groupings, the sample size 
is not increased in order to provide additional power for subset analyses.  
16.63 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 33% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
1 
1 
Not Hispanic or Latino 
12 
12 
24 
Ethnic Category: Total of all subjects 
12 
13 
25 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
2 
2 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
11 
10 
21 
Racial Category: Total of all subjects 
12 
13 
25 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


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17.0 
Pathology Considerations/Tissue Biospecimens  
17.1  
Summary Table of Tissue Specimens to be collected for this Protocol 
Type of tissue 
biospecimen to submit 
Mandatory 
or 
Optional 
When to submit 
Block, Slides, 
Core, etc. (# of 
each to submit) 
Reason for 
submission 
Process at 
site? (Yes 
or No) 
Temperature 
Conditions for 
Storage 
/Shipping 
All diagnostic slides 
from original biopsy 
Mandatory 
at baseline 
AND at the 
time of 
surgery 
At time of 
enrollment if 
available or 
biopsy at 
screening 
(Cohorts A&B) 
AND at time of 
surgery 
(Cohort A only) 
20 charged 
slides 5 microns 
thick sections 
(x2 sections per 
slide) 
Correlative 
studies for 
immune 
phenotyping 
Yes 
Refrigerated 
FFPE tissue blocks with 
corresponding H&E, OR 
unstained slides with 
corresponding H&E, 
from original biopsy 
Optional 
after 
chemo-
radiation 
and at end 
of treatment 
After chemo-
radiation  
AND at end of 
treatment 
1 block or 20 
charged slides 
5 microns thick 
sections 
(x2 sections per 
slide)  
Correlative 
studies for 
immune 
phenotyping 
Yes 
Refrigerated 
Fresh frozen tissue 
Optional 
At enrollment 
(Cohort B) and at 
time of surgery 
(Cohort A) or 
after chemo-
radiation (both 
cohorts) 
5-10 mm tissue 
piece obtained 
from either 
surgical 
specimen or 
core biopsy 
Correlative 
studies for 
immune 
gene 
expression 
studies 
Yes 
Frozen 




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Tissue Specimen Submission Form into the remote data entry system 
on the same day the specimen is submitted (see Forms Packet). A hard 
copy of the form must be submitted with the tissue. 
17.324 
Mayo Clinic Study Coordinator to obtain materials and work with 
study pathologist, Dr Michael Rivera, for review.  
17.33 Frozen Tissue 
17.331 
Optional, research obtained core biopsies of ATC tissues  pre and/or 
following initiation of pembrolizumab as indicated in the Table 17.1 
above, will be portioned into 5-10 mm pieces that will be frozen for 
immune gene expression studies. Frozen tissue cassettes will be stored 
in co-PI mentor’s lab of Dr. Allan Dietz, 3rd floor Stabile.   
17.332 
Please transport frozen tissue to Dr. Allan Dietz’s laboratory, 3rd floor 
Stabile building 
17.333 
Store frozen tissue in liquid nitrogen or -70 degree Celsius freezer 
17.4 
Background and Methodology 
ATCs have a high mutation burden, that when combined with chemoradiation, may lead 
to the elaboration of tumor neoantigens, thereby inducing susceptibility to anti-tumor 
immune responses following pembrolizumab therapy. Moreover, ATCs often develop 
from differentiated thyroid cancers (DTC), the latter of which are often associated, at 
least initially, with clinical and/or subclinical autoimmune thyroid disease (i.e. an anti-
thyroid response).  In DTCs, co-existent autoimmune thyroid disease, outcomes are 
generally favorable, suggesting an intact anti-thyroid/anti-tumor immune response. As 
DTCs progress to PDTC and ATCs, tumors become heavily infiltrated with TAMs that, 
together with acquired intrinsic tumor cell genetic alterations, promote an immune-
suppressive tumor microenvironment that permits rapid tumor progression. 
We hypothesize that the dynamic alterations in circulating and tumor infiltrating immune 
cell subtypes before and following chemoradiation plus pembrolizumab will inform 
clinical outcomes. This information will be used then as biomarkers to identify 
responders to pembrolizumab as well as to develop novel immune based combination 
strategies to overcome resistance among the non-responders. 
17.41 Immunohistochemical studies 
Immunohistochemical studies will be performed on FFPE sections pre and post 
pembrolizumab therapy to examine alterations in : 1) tumor infiltrating immune 
cells (i.e. T cells, TAMs, NK cells, DCs); 2) expression of MHC class expression 
proteins; 3) PD-1 and PD-L1 expression; 4) Ki67 proliferation index; and 
5) apoptosis markers. 
17.42 Gene expression studies 
Alterations in tissue-derived immune signatures through gene expression studies 
will be evaluated during the course of therapy to identify immune phenotypes 
associated with tumor responses and/or those associated with resistance to 
therapies. For example, altered cytokine expression levels, may induce and/or 
impair anti-tumor immune responses which can be used to identify responders as 
well as to develop novel immune therapy combinations for non-responders.  
 
 


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17.43 Thyroid autoantibody screens 
ATCs often develop from differentiated thyroid cancers (DTC), the latter of 
which are often associated, at least initially, with clinical and/or subclinical 
autoimmune thyroid disease (i.e. an anti-thyroid response).  In DTCs co-existent 
with autoimmune thyroid disease, overall outcomes are reportedly favorable from 
limited studies, suggesting the presence of an intact anti-tumor immune response. 
As DTCs progress, however, to PDTC and ATCs, tumors become heavily 
infiltrated with TAMs, that together with acquired intrinsic tumor cell genetic 
alterations, promote an immunosuppressive tumor environment and tumor escape 
from host-mediated anti-tumor control. We hypothesize that development of anti-
thyroid antibodies could predict the responders from non-responders when 
treated with pembrolizumab. 
17.44 Circulating tumor cells 
Circulating tumor cells load and decrease in their numbers have been shown to 
be prognostic markers in many cancers including breast (Cristofanilli, Budd et al. 
2004; Liu, Shields et al. 2009; Smerage, Barlow et al. 2014) and thyroid cancer 
(Xu, Handy et al. 2016). However, data from ATC is lacking and we will aim to 
prospectively collect circulating tumor cells and correlate with outcomes. The 
RareCyte CTC technology is a comprehensive, reproducible and highly sensitive 
dual-platform for collecting, identifying and analyzing CTCs that does not rely 
on EpCAM expression for enrichment. (Campton, Ramirez et al. 2015). This 
platform allows for mechanically precise CTC retrieval, enabling the isolation of 
DNA derived from single or pooled CTCs for advanced genomic analyses 
including the detection of specific mutations and targeted NGS. 
 


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18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Event monitoring 
See Section 4.0 and data submission table for the event monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s 
initials, MCCC registration number, and MCCC protocol number. Patient’s name 
must be removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for evidence of response to study 
therapy and progression after study therapy.  
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s 
initials, MCCC registration number, and MCCC protocol number. Patient’s name 
must be removed. 
18.7 
Incomplete materials 
Any materials deemed incomplete by the MCCC Operations Office will be 
considered “not received” and will not be edited or otherwise processed until the 
missing information is received. A list of the missing documents will be made 
available to the appropriate co-sponsor/participant. 
 
18.8 
Overdue lists 
A list of overdue materials and forms for study patients will be generated 
monthly. The listings will be sorted by location and will include the patient study 
registration number. The appropriate co-sponsor/participant will be responsible to 
obtain the overdue material. 
18.9 
Corrections forms 
If a correction is necessary the QAS will query the site. The query will be sent to 
the appropriate site to make the correction and return the query and 
documentation of correction back to the QAS.  
 
 
 


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19.0  
Budget 
19.1 
Costs charged to patient 
Routine clinical care costs will be the responsibility of the patient and/or the 
patient’s insurance company. This responsibility includes costs associated with 
surgery, radiation and with the administration of standard chemotherapy 
(doxorubicin and docetaxel). These drugs are commercially available and will be 
the responsibility of the patient and/or the patient’s insurance company. 
19.2 
Tests to be research funded 
• 
Correlative studies  
• 
Pembrolizumab administration 
• 
Collection, processing and storage of blood and tissue samples for future, 
unspecified research. 
19.3 
Other considerations 
Pembrolizumab will be provided by Merck & Co. 
 
 
 


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20.0 
References 
Ain, K. B., M. J. Egorin, et al. (2000). "Treatment of anaplastic thyroid carcinoma with paclitaxel: 
phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health 
Intervention Trials (CATCHIT) Group." Thyroid : official journal of the American Thyroid 
Association 10(7): 587-594. 
Akaishi, J., K. Sugino, et al. (2011). "Prognostic factors and treatment outcomes of 100 cases of 
anaplastic thyroid carcinoma." Thyroid : official journal of the American Thyroid Association 
21(11): 1183-1189. 
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MPDL3280A in cancer patients." Nature 515(7528): 563-567. 
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Kwon, J., B. H. Kim, et al. (2016). "The prognostic impacts of postoperative radiotherapy in the 
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in Patients with Metastatic Thyroid Cancer." The Journal of clinical endocrinology and 
metabolism: jc20162567. 
 
 
 
 


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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf stat.html 
 
 


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Appendix II 
New York Heart Association Classification of Congestive Heart Failure 
 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. 
no shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, 
e.g. walking short distances (20–100 m). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients. 
 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart 
Association. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the 
heart and great vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994. 
Original source: Criteria Committee, New York Heart Association , Inc.  Diseases of the Heart 
and Blood Vessels. Nomenclature and Criteria for diagnosis, 6th edition  Boston, Little, Brown 
and Co. 1964, p 114. 
 
 


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Appendix III Radiation Therapy Quality Control Guidelines 
 
1) Prescription dose and fractionation: 
 
Total administered prescription dose: 66 Gy 
Total number of fractions: 33 
 
2) Target coverage 
 
PTV6600 (photons) : V100 ≥ 95% and max dose (0.03 cc) ≤ 110% 
 
3) Normal tissue constraints 
 
Spinal cord: Max dose (0.03 cc) ≤50 Gy 
Parotid gland: mean dose to one of the parotid glands: <=26 Gy 
Oral cavity: mean dose <=25 Gy 
Submandibular glands: mean dose <=39 Gy 
Larynx: mean dose <=60 Gy 
Pharyngeal constrictors: mean dose <=54 Gy 
Esophagus: mean dose <=34 Gy 
Brachial plexus: maximum dose to 0.03 cc <=60 Gy unless overlapping with CTV then <=66 Gy 
Lung: percentage of lungs receiving 20 Gy <=20% 
 
 
4) Treatment duration/interruptions 
 
Elapsed days from first fraction to last fraction: ≤45 days 
 
Treatment plans/administration meeting all of the above criteria will be considered “per protocol.” 
Treatment plans/administration failing to meet one or more of the above criteria will be considered an 
“unacceptable deviation.” 
Dose Specifications  
Prescription dose shall be according to the following  
PTV66 (CTV66 + 5 mm margin) will receive 66 Gy in 33 fractions at 2 Gy per fraction. PTV59.4 
(CTV59.4 + 5 mm margin) will receive 59.4 Gy in 33 fractions at 1.8 Gy per fraction. All targets 
will be delivered simultaneously. Treatment will be delivered once daily, 5 fractions per week, 
over 6.5 weeks 
The reported doses for PTV66  shall include the prescription dose as well as the maximum point 
dose (maximum dose encompassing 0.03 cc volume) for that PTV, % PTV receiving ≥93%, 
≥110% and ≥115% of the prescription dose of that PTV, and the mean dose for that PTV. 
All plans shall be normalized such that ≥95% of the volume of PTV66 is covered by the 66 Gy 
isodose surface while more than >95% of the volume of PTV59.4 being covered by the 59.4 Gy 
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Technical Factors  
External Beam Equipment and Beam Delivery Methods 
Megavoltage equipment capable of delivering static intensity modulation a multileaf collimator or 
dynamic intensity modulation (using a multileaf collimator or tomotherapy), including VMAT is 
required.  
Treatment Planning, Imaging and Localization Requirements 
The immobilization device should at least include the head, neck, and shoulders. It is strongly 
encouraged to use a customized head and neck rest, Precise Bite, and indexed hand grips.   
Treatment planning CT scans will be required to define gross target volume(s), and clinical target 
volume(s). The treatment planning CT scan should be acquired with the patient in the same 
position and using the same immobilization device as for treatment. 
All tissues, including entire lung volumes (both lungs), to be irradiated must be included in the 
CT scan. CT scan thickness should be ≤0.2 cm slices through the region that contains the primary 
target volumes  including the top of the treatment table superiorly and the entire lung volumes 
inferiorly. 
The GTV and CTV, and normal tissues must be outlined on all CT slices in which the structures 
exist. 
Treatment Planning/Target Volumes  
The definition of volumes will be in accordance with the 1993 ICRU Report #50. 
The Gross Tumor Volume (GTV) is defined as all known gross disease determined from CT, 
MRI, PET/CT, clinical information, and endoscopic findings. Grossly positive lymph nodes are 
defined as any lymph nodes >1 cm or nodes with a necrotic center. It is strongly encouraged that 
the radiation oncologist outlines the radiologic extent of the primary tumor and neck nodes along 
with a radiologist. Whenever possible, it is recommended that the diagnostic images be fused to 
the planning CT scan image dataset to more accurately define the GTV. To further subdivide the 
GTV, gross disease at the primary site is designated as GTV-P and clinically involved gross 
lymph nodes are designated GTV-N. In situations where the patient underwent surgery prior to 
radiation therapy, the GTV is defined as the preoperative gross disease plus the post-operative 
surgical bed. 
The Clinical Target Volume (CTV): See the bulleted list below for delineation details. 
For patients without complete surgical resection: In terms of the GTV (GTV-P and GTV-N), a 
margin of ≥ 10 mm should be given circumferentially around the GTV (GTV-P and GTV-N) and 
this volume will be called the CTV66 (CTV66-P and CTV66-N).* This margin can be reduced to 
as low as 1 mm for tumors in close proximity to critical structures, e.g., tumors next to the spinal 
cord. For regions deemed to be at high risk for microscopic disease, all potential routes of spread 
for primary and nodal GTVs should be delineated by the treating radiation oncologist. This is 
known as CTV for subclinical disease or CTV59.4*  CTVs will not include air or normal adjacent 
organs that have not been invaded (cartilage, bone, brachial plexus, etc.) 
• 
For patients who have undergone a complete surgical resection: CTV66 should include the 
preoperative gross disease at the primary disease site or any grossly involved lymph nodes as 
well as the post-operative bed. A CTV59 4 also can be delineated if the region is at risk for 
microscopic spread and the region has not had surgery. 
• 
To further define the subclinical region at risk for microscopic spread at the primary disease 
site, CTV59 4-P includes CTV66-P + ≥5 mm margin and ensuring that the following is 
generously covered: tracheal-esophageal groove, levels II-VI, and upper mediastinal nodes  to 






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Treatment plans will be scored as Per Protocol, Variation Acceptable, or Deviation Unacceptable. 
It is encouraged to generate treatment plans that fall within the dose limits defining the per 
protocol category (see tables below). For those target to critical structures geometries that are 
more challenging, some variation from the per protocol dose limits is acceptable. The variation 
acceptable dose limits are given in the table below. Plans that fall outside of the variation 
acceptable dose limits are scored as deviation unacceptable. 
 
Per 
Protocol 
Variation 
Acceptable 
Variation 
Unacceptable 
PTV_6600  
Total RT dose to 95% of the PTV_6600  
66 Gy  
66 Gy - 62.7 
Gy  
<62.7 Gy  
Percentage of PTV_6600 receiving 61.4 
Gy (93% of 66 Gy)  
≥99%  
≥97%  
≤97%  
Percentage of PTV_6600 receiving 72.6 
Gy (110% of 66Gy)  
≤20%  
≤40%  
≥40%  
Percentage of PTV_6600 receiving 75.9 
Gy (115% of 66 Gy) 
≤5%  
<20%  
≥20%  
Mean dose of PTV_6600  
≤70.4 Gy  
70.4 -72.6 Gy  
≥72.6 Gy  
 PTV_5940 (photons) 
Total RT dose to 95% of PTV_5940  
59.4 Gy  
59.4 -56.4 Gy  
<56.4 Gy  
Percentage PTV_5940 receiving 55.2 Gy 
(93% of 59.4 Gy)  
≥99% Gy  
≥97%  
≤97%  
 
Acceptable Dose Limits on Critical Structures for Plan Scoring 
Critical Normal Tissue 
Maximum dose to 0.03 cc of SpinalCord  
≤45 Gy  
45 - 48 Gy  ≥48 Gy  
Maximum dose to 0.03 cc of 
SpinalCord_05  
≤50 Gy  
50-54 Gy  
≥54 Gy  
Mean dose to one of Parotid glands  
≤26 Gy  
 
 
50% of one of the Parotid glands  
 
≤30 Gy  
≥30 Gy  
20 cc of both parotids  
 
≤20 Gy  
≥20 Gy  
Percentage of Lungs receiving 20 Gy  
≤20%  
≤25%  
≥25%  
 
Suggested Dose Limits Not for Plan Scoring (Should Not Compromise 
Tumor Volume Coverage) 
Oral cavity (excluding PTVs)  
Mean dose ≤25 Gy  
Submandibular glands  
Mean Dose ≤39 Gy  
Larynx  
Mean dose ≤60 Gy  
Maximum dose to 1cc of un-specified Tissue  
≤69.3 Gy  
Maximum dose to 0.03cc of Brachial Plexus 
≤60 Gy  
Maximum dose to 0.03cc of Brachial Plexus 
when Tumor Volume is overlapped with Brachial 
Plexus 
≤66 Gy 
Esophagus 
Mean ≤34 Gy 
Pharyngeal constrictors 
Mean ≤54 Gy 
 
 


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Appendix IV Pembrolizumab ECI Drug-Induced Liver Injury (DILI) 
Hepatotoxicity is injury or damage to the liver that may be associated with impaired liver 
function (Navarro and Senior 2006). Drug-induced hepatotoxicity is one of the most common 
causes of termination of drug development, a major reason for refusal of market authorization 
and for restricted use, and the single most important cause of the withdrawal of market 
authorization for products (Björnsson 2006). Thus, drug-induced hepatotoxicity is a major 
concern during the discovery, development to postauthorization phases of the product life cycle 
(excerpted from Draft Guidance Document, Hepatotoxicity of Health Products, Ministry of 
Public Health, Canada, December 2010). 
As stated in the United States Food and Drug Administration (FDA) Guidance for Industry - 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation; hepatocellular injury (usually 
detected by serum aminotransferase elevations [AT]) can be caused by drugs that rarely, if ever, 
cause severe DILI (e.g. aspirin, tacrine, statins, and heparin) as well as by drugs that do cause 
such injury. The frequency of serum AT elevations also is not a good indicator of a potential for 
severe DILI, because drugs such as tacrine (not a cause of severe DILI) can cause AT elevations 
in as many as 50 percent of patients. Very high levels of observed ATs may be a somewhat 
better indicator of potential for severe DILI, but the most specific indicator is evidence of altered 
liver function accompanying or promptly following evidence of hepatocellular injury. 
The single clearest (most specific) predictor found to date of a drug’s potential for severe 
hepatotoxicity, is the occurrence of hepatocellular injury (AT elevation) accompanied by 
increased serum total bilirubin (TBL), not explained by any other cause, such as viral hepatitis or 
exposure to other hepatotoxins, and without evidence of cholestasis, together with an increased 
incidence of AT elevations in the overall trial population compared to control. Increased plasma 
prothrombin time, or its international normalized ratio (INR), a consequence of reduced hepatic 
production of Vitamin K dependent clotting factors, is another potentially useful measure of liver 
function that might suggest the potential for severe liver injury. 
Recognition of the importance of altered liver function, in addition to liver injury, began with 
Hyman Zimmerman’s observation that drug-induced hepatocellular injury (i.e. AT elevation) 
accompanied by jaundice (i.e. TBL elevation) had a poor prognosis, with a 10 to 50 percent 
mortality from acute liver failure (in pretransplantation days) (Zimmerman 1978, 1999). This 
became known as "Hy's Law". This document describes the recommended process for 
monitoring and evaluation of subjects meeting the laboratory criteria for potential DILI defined 
as: 
• 
an elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater 
than or equal to three times (3X) the upper limit of normal (ULN)  
and 
• 
an elevated total bilirubin (TBL) lab value that is greater than or equal to two times (2X) ULN 
and 
• 
at the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 
as a result of within-protocol-specific testing or unscheduled testing. 
The protocol identifies these laboratory criteria for potential DILI as ECIs. ECIs are selected 
adverse experiences that must be reported within 24 hours. 
Initiate close observation as defined below and continue follow-up until resolution. 


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• 
Repeat liver enzyme and serum bilirubin tests two (2) or three (3) times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or study drug has been 
discontinued and the subject is asymptomatic. 
• 
Obtain a more detailed history of symptoms and prior or concurrent diseases. 
• 
Obtain a history of concomitant medication use (including prescription and nonprescription 
medications, herbal and other dietary supplements), alcohol use, recreational drug use and special 
diets. (See Section 5 for details.) 
• 
Obtain a history of exposure to chemical agents or other environmental toxins. 
• 
Obtain additional history and complete Stage 1 workup to attempt to rule out other potential 
causes of the transaminase elevation, including but not limited to the following: acute viral 
hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; non-alcoholic steatohepatitis 
(NASH); hypoxic/ischemic hepatopathy; and biliary tract disease 
• 
Consider gastroenterology or hepatology consultation 
 


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Appendix V 
Presentation of Dermatologic Event 
Collect information on clinical presentation and potential contributing factors. Key information 
should be summarized and entered on the Adverse Experience CRF. Any treatments 
administered should be entered in the medical record. Scan and forward this form to Principal 
Investigator. 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug? 
____________________________________________________________________________ 
2. Has the subject contacted any known allergens? □ Yes □ No 
If so what kind?  _______________________________________ 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, 
soap, personal care product, poison ivy, etc.)? □ Yes □ No 
If so what kind?  _______________________________________ 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and 
supplement)? □ Yes □ No 
If so what kind?  _______________________________________ 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No 
If so what kind?  _______________________________________ 
6. Does the subject have or had in the last few days any illness? □ Yes □ No 
If so what kind?  _______________________________________ 
7. Has the subject come into contact with any family or house members who are ill?  
□ Yes □ No 
If so what kind?  _______________________________________ 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash 
(e.g. Molluscum Contagiosum)? □ Yes □ No 
9. Has the subject had recent sun exposure? □ Yes □ No 
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No 
If so what kind?  _______________________________________ 
i. Anaphylaxis? □ Yes □ No 
ii. Signs of hypotension? □ Yes □ No  


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iii. Signs of dyspnea? □ Yes □ No 
iv. Fever, night sweats, chills? □ Yes □ No 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic 
catecholamine therapy? □ Yes □ No 
If so what kind?  _______________________________________ 
 
12. For the current rash, has the subject used any other medication, such as inhaled 
bronchodilators, antihistaminic medication, topical corticosteroid, and/or systemic 
corticosteroid? □ Yes □ No 
List medication(s) and dose(s):  _______________________________________ 
13. Is the rash pruritic (itchy)? □ Yes □ No 
Focused Skin Examination 
Focused Skin Examination: 
Key information should be summarized and entered on the Adverse Experience CRF. 
 
Primary Skin Lesions Description 
Color: _______________________________________ 
 
General description: 
_________________________________________________________________ 
_________________________________________________________________ 
 
Describe the distribution of skin reaction, skin eruption, or rash on the body: 
_________________________________________________________________ 
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
_________________________________________________________________ 
 
Any associated signs on physical examination? 
_________________________________________________________________ 
 
 
Scan this form and forward by email to the Principal Investigator listed on the cover page of the 
protocol.