Conditions: Cutaneous Squamous Cell Carcinoma Advanced Cancer
Keywords: Cutaneous Squamous Cell Carcinoma Advanced Cancer Allogeneic hematopoietic stem cell transplant Kidney transplant
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12
Healthy volunteers: no

Brief summary:
In this research study, Cemiplimab is being evaluated as a treatment for advanced cutaneous squamous cell carcinoma in participants who have previously received an allogeneic hematopoietic stem cell transplant or kidney transplant.

\- This research study involves the following drug(s):

* Cemiplimab
* Everolimus or Sirolimus
* Prednisone

Detailed description:
* This an open-label, two cohort, phase I/II research study to evaluate the safety and effectiveness of Cemiplimab as a treatment for advanced cutaneous squamous cell carcinoma in participants who have received allogeneic hematopoietic stem cell or kidney transplants.
* The research study procedures include screening for eligibility, study treatment, participant evaluations and safety follow-up visits. It is expected that about 12 people will take part in this research study.

  * Participants will be divided into two groups (cohorts) of allogeneic hematopoietic stem cell recipients or kidney transplants recipients.
  * Allogeneic hematopoietic stem cell recipients will only receive the study treatment drug of Cemiplimab.
  * Kidney transplant recipients will receive the study treatment drug of Cemiplimab along with the immunosuppressant drugs of Everolimus or Sirolimus and Prednisone to prevent kidney rejection.

The U.S. Food and Drug Administration (FDA) has approved Cemiplimab as a treatment option for patients with advanced cutaneous squamous cell cancer, but the FDA has not approved the use of Cemiplimab in participants who have received allogeneic hematopoietic stem cell transplants or kidney transplants in the past.

\-- Cemiplimab is a type of drug called a monoclonal antibody. Antibodies are proteins naturally found in your blood that fight infections. A monoclonal antibody is a special kind of antibody that is manufactured as a medication to target specific proteins in the body that may be involved this type of cancer.

Cemiplimab is a human monoclonal anti-PD-1 antibody that works by blocking the programmed death-1 (PD-1), a cell receptor on immune cells that is involved in preventing immune cells from destroying other cells. Blocking the receptor is expected to help immune cells attack cancer cells.

Arms:
arm 1: Participants who received allogeneic hematopoietic stem cell transplant

\-- Cemiplimab: via IV, flat predetermined dosage every 21 days arm 2: Participants who received a kidney transplant will receive

* Cemiplimab via IV, flat predetermined dosage every 21 days
* Everolimus or Sirolimus-least 7-10 days prior to receiving the first dose of cemiplimab (Cycle 1, Day 1) and then daily while receiving Cemiplimab
* Prednisone 40 mg orally the day prior to the start of cemiplimab dosing (Cycle 1, Day 1) and then daily at tapering doses while receiving Cemiplimab

Interventions: intervention 1: Cemiplimab intervention 2: Everolimus intervention 3: Sirolimus intervention 4: Prednisone
Intervention descriptions: intervention 1: Cemiplimab: via IV, flat predetermined dosage every 21 days. intervention 2: Everolimus at least 7-10 days prior to receiving the first dose of cemiplimab (Cycle 1, Day 1) and then daily while receiving Cemiplimab intervention 3: Sirolimus at least 7-10 days prior to receiving the first dose of cemiplimab (Cycle 1, Day 1) and then daily while receiving Cemiplimab intervention 4: 40 mg orally the day prior to the start of cemiplimab dosing (Cycle 1, Day 1) and then daily at tapered dosing while receiving Cemiplimab

Protocol document:
Prot_000.pdf: 
NCI Protocol #: Not applicable 
 
DF/HCC Protocol #: 19-817 
 
TITLE: A Phase I/II Study of the Safety and Efficacy of Cemiplimab (PD-1 blockade) in 
Selected Organ Transplant Recipients with Advanced Cutaneous Squamous Cell 
Carcinoma (CONTRAC) 
 
 
Coordinating Center: 
Dana-Farber Cancer Institute, 
450 Brookline Avenue, Boston, MA 02215 
 
 
*Principal Investigator (PI): 
Glenn J. Hanna, M.D. 
Dana-Farber Cancer Institute 
glenn_hanna@dfci.harvard.edu 
 
Other Investigators: 
Ann W. Silk, M.D. 
Dana-Farber Cancer Institute 
ann_silk@dfci.harvard.edu 
 
Naoka Murakami, M.D., Ph.D. 
Brigham & Women’s Hospital 
nmurakami1@bwh.harvard.edu 
 
 
 
Agent: Cemiplimab 
Other Agents: Everolimus, Sirolimus, Prednisone 
 
IND Holder: Glenn J. Hanna, M.D. 
 
 
Protocol Type / Version # / Version Date: May 3, 2023 
 
Statistician: 
Anita Giobbie-Hurder 
Dana-Farber Cancer Institute 
450 Brookline Ave, Boston MA 02215 
Robert_redd@dfci.harvard.edu 
P: 617-632-6455 F: 617-632-2516 
 
 
 
 
 
 
 
 
 
 
Page 1 


NCI Protocol #: N/A 
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Protocol Version Date: May 3, 2023 
2 
 
 
Responsible Research Nurses 
John Harran, RN 
Dana-Farber Cancer Institute 
450 Brookline Ave, Boston MA 02215 
John_Harran@dfci.harvard.edu 
P: 617-632-6042 F: 617-632-6727 
Zixi Liao, RN 
Dana-Farber Cancer Institute 
450 Brookline Ave, Boston MA 02215 
Zixi_Liao@dfci.harvard.edu 
P: 617-632-6042 F: 617-632-6727 
IND #: 146156 
IND Sponsor: Glenn Hanna, MD 


NCI Protocol #: N/A 
DF/HCC Protocol #: 19-817 
Protocol Version Date: May 3, 2023 
3 
 
 
Cemiplimab IV 
every 21 days 
Cohort 2: renal transplant recipient 
R 
e 
g 
i 
s 
t 
r 
a 
t 
i 
o 
n 
Cemiplimab IV 
every 21 days 
Patients with advanced or metastatic 
cutaneous squamous cell carcinoma 
(cSCC) 
Key Eligibility: 
•Histologically confirmed 
diagnosis of cSCC 
•1 or more measurable lesions (≥ 
1 cm) 
•History of allogeneic 
hematopoietic stem cell 
transplant (HSCT), Cohort 1 
✓≥ 2 years (730 days) from 
the time of transplant 
✓Off of all systemic 
immunosuppression ≥ 3 
months prior to 
enrollment 
✓Prior acute GVHD that 
has resolved, or sequelae 
of chronic GVHD are 
both permitted 
•History of renal allograft 
transplant, Cohort 2 
✓Renal function: estimated 
glomerular filtration rate 
(GFR) by CKD-EPI 
equation ≥ 30 mL/min 
✓No significant proteinuria 
✓Off antiproliferative 
immunosuppressants 
•ECOG PS ≤ 2 
•No prior PD-1/L1 inhibitors 
•No active autoimmune disease 
1 cycle=21 days 
* mTOR initiation may require a 7-10 day lead-in 
prior to cemiplimab dosing if the subject is on 
alternative immunosuppressive agents 
** prednisone is dose at 40 mg daily starting on 
day -1 of the study prior to cemiplimab dosing 
Screening 
Treatment 
End of Treatment (EOT) 
F/U 
Cohort 1: allogeneic HSCT recipient 
Everolimus twice daily or 
Sirolimus daily* 
and 
Prednisone (pulse dosing) daily** 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
until unacceptable toxicity 
(GVHD) or progression 
until unacceptable toxicity 
(organ rejection) or 
progression 
30 day 
f/u visit 
then 
every 
3-4 
months 
up to 1 
year 


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Protocol Version Date: May 3, 2023 
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TABLE OF CONTENTS 
SCHEMA ................................................................................................................................ 3 
1. 
OBJECTIVES ...................................................................................................................... 6 
1.1 
Study Design ............................................................................................................ 6 
1.2 
Primary Objectives ................................................................................................... 6 
1.3 
Secondary Objectives ............................................................................................... 6 
2. 
BACKGROUND .................................................................................................................. 6 
2.1 
Study Disease(s) ....................................................................................................... 6 
2.2 
IND Agents .................................................+ ................................................................................ 8 
2.3 
Rationale................................................................................................................. 13 
2.4 
Correlative Studies Background ............................................................................. 14 
3. 
PARTICIPANT SELECTION ........................................................................................... 15 
3.1 
Eligibility Criteria .................................................................................................. 15 
3.2 
Exclusion Criteria ................................................................................................... 16 
3.3 
Inclusion of Women and Minorities ....................................................................... 18 
4. 
REGISTRATION PROCEDURES .................................................................................... 18 
4.1 
General Guidelines for DF/HCC Institutions ......................................................... 18 
4.1 
Registration Process for DF/HCC Institutions ....................................................... 18 
5. 
TREATMENT PLAN ........................................................................................................ 18 
5.1 
Treatment Regimen ................................................................................................ 18 
5.2 
Pre-Treatment Criteria............................................................................................ 20 
5.3 
Agent Administration ............................................................................................. 20 
5.4 
General Concomitant Medication and Supportive Care Guidelines ...................... 21 
5.5 
Criteria for Taking a Participant Off Protocol Therapy ......................................... 22 
5.6 
Duration of Follow-Up ........................................................................................... 22 
5.7 
Criteria for Taking a Participant Off Study ............................................................ 22 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................ 23 
6.1 
Cemiplimab ............................................................................................................ 23 
6.2 
Dynamic Immunosuppression ................................................................................ 25 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................. 25 
7.3 
Adverse Event Reporting ...................................................................................... 27 
Serious Adverse Events ...................................................................................................... 27 
7.4 
Reporting to the Food and Drug Administration (FDA) .................................... 28 
7.5 
Reporting to Hospital Risk Management ........................................................... 28 


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7.6 
Routine Adverse Event Reporting.........................................................................28 
Serious Adverse Events ..................................................................................................... 29 
7.6.1 Acute GVHD Adverse Event Grading (Cohort 1) ....................................................30 
7.6.2 Diagnostic Criteria for Chronic GVHD (Cohort 1) ..................................................30 
7.6.3 Suspected Acute renal allograft rejection (Cohort 2) ................................................31 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................32 
8.1 
Cemiplimab ........................................................................................................... 32 
Free of cost, investigational supply of cemiplimab, will be provided by Regeneron 
pharmaceuticals ..................................................................................................................33 
8.2 
Other Agents ......................................................................................................... 33 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 33 
9.1 
Laboratory Correlative Studies ............................................................................. 33 
10. 
STUDY CALENDAR ....................................................................................................... 35 
11. 
MEASUREMENT OF EFFECT ........................................................................................38 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................38 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ........................................... 44 
12.1 
Data Reporting .......................................................................................................44 
12.2 
Data Safety Monitoring ..........................................................................................44 
13. 
STATISTICAL CONSIDERATIONS. ..............................................................................44 
13.1 
Study Design/Endpoints .........................................................................................45 
13.2 
Stratification Factors ............................................................................................. 45 
13.3 
Analysis of Primary Endpoints.............................................................................. 45 
13.4 
Analysis of Secondary Endpoints.......................................................................... 46 
14. 
PUBLICATION PLAN ..................................................................................................... 46 
REFERENCES .............................................................................................................................. 47 
APPENDIX A 
CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION 
(CKD-EPI) EQUATION ................................................................................................... 50 
APPENDIX B 
PERFORMANCE STATUS CRITERIA .................................................. 51 
APPENDIX C 
GUIDANCE ON CONTRACEPTION ..................................................... 52 
appendix D 
IMMUNE-MEDIATED TOXICITY MANAGEMENT ALGORITHMS ........... 53 
appendix E 
NIH CONENSUS FORM for SCORING CHRONIC GVHD .............................. 61 


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1. OBJECTIVES 
 
1.1 
Study Design 
 
This is an open-label, two cohort, phase I/II study of immune checkpoint blockade with 
cemiplimab in patients with advanced cutaneous squamous cell carcinoma (cSCC) who have 
previously undergone an allogeneic hematopoietic stem cell transplant (HSCT) or renal allograft 
transplantation. Patients are divided into two cohorts based on their history of prior HSCT for a 
lymphoproliferative disorder or hematologic malignancy (Cohort 1), and a history of prior renal 
transplantation (Cohort 2). In the rare event that a patient has a history of both prior HSCT and 
prior renal transplantation, the patient would be included in Cohort 2. Following biopsy, 
screening, and enrollment, participants in Cohort 1 receive cemiplimab at standard dosing (350 
mg IV every 21 days) until disease progression or unacceptable toxicity (including graft-versus- 
host disease [GVHD]), whichever occurs first. Cohort 2 mandates that the patient follow a 
standard immunosuppressive regimen that includes: everolimus or sirolimus with monitored 
trough levels to ensure therapeutic levels, in addition to prednisone pulse dosing corresponding 
to each dose of cemiplimab (prednisone 40 mg daily 1 day prior to cemiplimab, followed by 40 
mg daily on the day of and up to 2 additional days after dosing, then 20 mg for 3 days, followed 
by 10 mg daily thereafter until the day prior to redosing of cemiplimab when the prednisone 
cycle repeats). Prophylactic antibiotics are permitted at the discretion of the treating physician 
while the patient is on immunosuppression and for the duration of the study. Treatment continues 
in Cohort 2 with cemiplimab at standard dosing (350 mg IV every 21 days) until unacceptable 
toxicity (acute allograft rejection) or disease progression. Our aim is to evaluate the safety and 
efficacy of cemiplimab in this high-risk but in-need population, and utilize a standard, 
augmented immunosuppression regimen to minimize the risk of immune-related toxicity, 
specifically organ transplant rejection. 
 
1.2 
Primary Objectives 
 
To determine the safety and toxicity of immunotherapy in advanced cutaneous squamous cell 
carcinoma (cSCC) patients having undergone prior hematopoietic stem cell or renal transplant. 
 
1.3 
Secondary Objectives 
 
To evaluate the anti-tumor activity and survival benefit in advanced cSCC patients receiving 
immunotherapy despite a history of transplant: 
• To estimate progression-free survival (PFS) and overall survival (OS) 
• To estimate overall response rate (ORR) 
• To estimate duration of therapeutic response 
• To estimate the propensity for secondary infection on treatment 


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2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Cutaneous squamous cell carcinoma (cSCC) is diagnosed in hundreds of thousands of patients 
each year in the United States and continues to increase due to our aging and sun-exposed 
population [1]. Risk factors for cSCC include sun or ultraviolet (UV) radiation exposure, 
advanced age, and immunosuppression [2]. The vast majority of cases are localized to the skin 
and treatment is with curative intent but, compared with other non-melanomatous skin cancers 
cSCC in immunosuppressed populations, can result in a greater propensity for aggressive 
recurrence and metastatic involvement [3]. Standard treatments involve surgery with the goal of 
oncologic resection (including sizeable excisional margins) with a role for adjuvant radiotherapy 
favored among patients with intermediate-to-high risk features such as nodal involvement, 
perineural invasion, significant depth of invasion, and large tumor size – with 5-year survival 
estimated at 73% in those receiving radiation vs. surgery alone (54%), and mitigating 
locoregional recurrence rates (20% vs. 43%) in this scenario [4]. Host factors such as the 
immunocompetence of the patient and whether the lesion in question represents a recurrence are 
other important considerations when considering adjuvant radiation to prevent locoregional 
relapse. 
 
When unresectable or advanced, metastatic cSCC develops, prior to 2018 there had previously 
been no standard systemic regimen when considering platinum-based chemotherapy and 
epidermal growth factor receptor (EGFR) targeting antibodies due to a lack of robust safety and 
efficacy data in large, prospective, multicenter trials. Rather, single-arm studies often reported 
benefit among a heterogeneous cSCC population with much extrapolation from head and neck 
SCC data. Cisplatin and 5-fluorouracil-based regimens have shown some efficacy but with 
notable rates of toxicity (76% of cSCC patients with grade 3+ adverse events) [5]. The EGFR 
inhibitor cetuximab has demonstrated a 28% overall response rate with a median OS of 8 months 
[6], and a similar antibody (panitumumab) demonstrated 31% response rates [7]. Across the 
board, response rates for systemic cytotoxic and antibody-directed therapies in advanced cSCC 
have ranged from 17-50% and seem to be muted in patients with more widespread disease [8]. 
 
Until 2018, no systemic therapies were approved for the treatment of advanced cSCC, as 
mentioned above. Because of a robust UV driven mutational burden and the link with 
immunosuppression, there was a strong interest in exploring immunotherapies in this disease. 
Cancer medicine has been revolutionized by the advent of immune checkpoint blockade agents 
that serve to block T cell inhibitory signaling and thereby promote T cell activation through 
receptors like programmed cell death-protein 1 (PD-1) and its ligand (PD-L1) on tumor and 
surrounding immune cells [9]. Recently, a landmark phase I/II study demonstrated that the 
highly potent PD-1 inhibitor cemiplimab (formerly REGN2810) resulted in 47-50% overall 
response rates among advanced cSCC patients; with the duration of response exceeding 6 
months in more than half of patients [10]. Neither median PFS nor OS had been reached at that 
time of reporting, but the estimated PFS at 1-year was 53% and 1-year OS 81%. Adverse events 
were manageable with 15% of patients experiencing immune-mediated side effects such as rash, 
diarrhea, and fatigue. These data led to Food and Drug Administration (FDA) approval of 
cemiplimab in September 2018. 


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Despite the success of immune checkpoint blockade in advanced cSCC, there are some important 
groups excluded from immunotherapy trials in general. Non-melanomatous skins cancers, 
particularly cSCC, represents a major cause of morbidity following organ transplantation – with 
SCC representing the most common cutaneous malignancy in this setting with a 65-100 fold 
greater incidence among organ transplant recipients compared with the general population [11]. 
Because of their ongoing need for some component of long-term immunosuppression, their 
competing medical issues, and the concern for off-target immune toxicity jeopardizing their 
transplanted organ, these patients have been excluded from immunotherapy trials despite the 
devastation and mortality of advanced cSCC in these transplant survivors – where 3-year 
disease-specific survival may only approach 50% [12]. 
 
2.2 
IND Agents 
 
2.2.1 
Cemiplimab 
 
2.2.1.1 
Mechanism of action and pharmacology 
 
Cemiplimab-rwlc is a recombinant human IgG4 monoclonal antibody that inhibits programmed 
death-1 (PD-1) activity by binding to PD-1 and blocking the interactions with the ligands PD-L1 
and PD-L2, releasing PD-1 pathway-mediated inhibition of immune response, including anti- 
tumor response. PD-1 ligand upregulation may occur in some tumors and signaling through this 
pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Blocking 
PD-1 activity has resulted in decreased tumor growth. Cemiplimab has a volume of distribution 
of 5.3L and a half-life elimination of 19 days with renal clearance (first dose: 0.32 L/day, steady 
state: 0.21 L/day). 
 
2.2.1.2 
Clinical safety 
 
Cemiplimab was investigated in a phase I/II open-label trial in advanced cSCC patients where 
the most common adverse events were diarrhea (27% of patients), fatigue (24%), nausea (17%), 
constipation (15%), and skin rash (15%) [10]. Four patients (7% of the initial study) discontinued 
therapy due to adverse events. Grade 3 toxicity or higher events that occurred in >1 patient 
included cellulitis, pneumonitis, hypercalcemia, pleural effusion, and death. Overall there were 
11 deaths in the original phase I/II study, 8 attributed to disease progression, and 3 from adverse 
events. 
 
In terms of safety after allogeneic hematopoietic stem cell transplantation (allo-HSCT), Herbaux 
and colleagues reported on 20 relapsed Hodgkin lymphoma (HL) patients treated with another 
PD-1 inhibitor, nivolumab [13] (Table 1, below). GVHD occurred in 6 patients (30%) after 
nivolumab initiation, but all had a prior history of acute GVHD. Overall response rate was 95% 
and the 1-year PFS was 58% and OS 79%. All cases of PD-1 triggered acute GVHD occurred 
within 1 week of the first dose. There were no reported cases of chronic GVHD among the 
cohort. Time between allo-HSCT and nivolumab treatment was significantly shorter in patients 
with PD-1 triggered GVHD (median of 8.5 months). All patients were successfully managed 
with standard GVHD treatments. In another study evaluating relapsed lymphoma patients post- 


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9 
 
 
allo-HSCT, Haverkos and colleagues reported anti-PD-1 inhibitor use in 31 patients with a 
response rate of 77% overall but n = 8/31 (26%) developed significant GVHD after anti-PD-1 
dosing, with an onset between 1-2 doses [14]. The majority of cases were among those with prior 
acute GVHD or active chronic GVHD. 
There is also emerging data about allo-HSCT patients who have previously received immune 
checkpoint blockade for lymphoma after autologous HSCT. A report of 39 patients with 
lymphoma who had prior PD-1 inhibition before allo-HSCT showed that at a median of 12 
month follow-up, 1-year cumulative rates of grade 3-4 GVHD were 23%, but the overall survival 
at 1-year was excellent at 89% [15]. 
 
Table 1. Retrospective studies using PD-1 blockade after allogeneic HSCT 
Study 
Diagnosis/ 
Treatment 
# 
Therapy 
+GVHD 
Post-PD-1 
Prior 
aGVHD 
Prior 
cGVHD 
Time between 
allo-HSCT 
and PD-1i 
Haverkos 
BM, et al. 
2017 
Lymphoma; 
allo-SCT with relapse 
31 
Nivolumab, 
pembrolizumab 
17 (55%)A 
3 (18%) 
9 (53%) 
-- 
Herbaux C, 
et al. 
2017 
Hodgkin lymphoma, 
allo-SCT with relapse 
20 
Nivolumab 
6 (30%) 
6 (100%) 
1 (17%) 
8.5 monthsB 
A all GVHD occurred after ≤ 2 PD-1 inhibitor doses except in 1/17 patients; GVHD occurred most often in matched sibling 
donor transplant cases; 
B median time from allo-HSCT to PD-1 blockade among those patients who did not experience GVHD was 28.5 months 
 
In terms of PD-1 blockade in organ transplantation recipients, data is limited to case reports to- 
date given the concern for acute organ rejection and ongoing immunosuppression needs. Herz 
and colleagues reported a renal transplant recipient treated with tacrolimus and prednisolone who 
received the anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) antibody ipilimumab, 
another immune checkpoint inhibitor, and later received PD-1 blockade with single-agent 
nivolumab [16]. Neither PD-1 or CTLA-4 inhibition triggered renal allograft rejection and the 
patient had clinical benefit from the therapy. Several studies summarized in Table 2 below have 
reported success and failure with allograft tolerance following checkpoint inhibitor use, but the 
actual rates of rejection are not known. An important observation among these reports is that in 
two series (Lesouhaitier, et al. 2018; Barnett, et al. 2017) [17, 18], all of the patients in the anti- 
PD-1 use post-renal transplant group who did not experience organ rejection had been on 
mechanistic target of rapamycin (mTOR) inhibition as part of immunosuppression. Abdel- 
Wahab and colleagues recently published the largest series to date of 23 renal transplant 
recipients who received various checkpoint inhibitors (PD-1/CTLA-4 directed, or both) and 
11/23 (48%) experienced acute kidney rejection within a median of 21 days (range: 5-60 days) 
from transplantation [19]. Of note, the immunosuppressive regimen was quite variable among 
this retrospective group and included steroids, mTOR inhibitors, CNIs, and combinations of 
these agents without standardization. 
 
Table 2. Case reports and series using immune checkpoint blockade after kidney transplant 
Report 
Diagnosis 
# 
Therapy 
Kidney Rejection 
IS agents 
Median 
Post-PD-1 
Time 
between 
kidney 
transplant 
and PD-1i 


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Ong, et al. 
2016 
Melanoma 
1 
Nivolumab 
Yes 
Tacrolimus, 
prednisone, MMF 
(tapered prior to PD-1i) 
10 years 
Herz, et al. 
2016 
Melanoma 
1 
Ipilimumab, 
Nivolumab 
No 
Tacrolimus + 
prednisone 
-- 
Spain, et al. 
2016 
Melanoma 
1 
Nivolumab (after 
ipilimumab) 
Yes 
Prednisolone 
12 years 
Kwatra, et al 
2017 
Melanoma 
1 
Pembrolizumab 
Yes 
Tacrolimus + MMF 
13 years 
Barnett, et 
al. 2017 
Renal cell 
carcinoma 
1 
Nivolumab 
No 
Everolimus + 
prednisone 
-- 
Lesouhaitier, 
et al. 2018 
NSCLC, 
Melanoma, 
Merkel cell 
7 
Nivolumab, 
Ipilimumab, 
Pembrolizumab, 
or Avelumab 
Yes = 3 
No = 4 
Steroids, MMF, 
mTORi (4 non- 
GVHD); tacrolimus, 
MMF, cyclosporine 
(3 with GVHD) 
1-3 months 
Tio, et al. 
2018 
Melanoma 
5 
Pembrolizumab, 
Nivolumab, 
Ipilimumab 
Yes = 1 
No = 4 
Steroids, MMF, 
tacrolimus, mTORi (4 
non-GVHD); tacro, 
steroid (1 with GVHD) 
-- 
Abdel- 
Wahab, et 
al. 2019 
Solid 
tumors 
23 
Pembrolizumab, 
Nivolumab, 
Ipilimumab 
Yes = 4 
No = 19 
mTOR inhibitor (n = 
11), steroids (n = 23), 
Tacrolimus, 
cyclosporin (n = 19) 
9 years (0.3- 
32 years) 
2.2.1.3 
Clinical efficacy 
 
In the pivotal phase I/II trial of cemiplimab in advanced or metastatic cSCC patients the overall 
response rate was 47% and the rate of durable disease control was 61% with 4 complete 
responses and 24 partial responses [10]. Median time to an observed response was 1.9 months 
(range, 1.7-6.0 months), and the median duration of response had not been reached at the time of 
reporting. However, 57% of patients with a response had a duration of benefit that exceeded 6 
months in their analysis. Only 3 patients had subsequent disease progression following 
confirmed response, and at the time of data cutoff 82% of responders continued to benefit and 
continued on PD-1 blockade. Both median PFS and OS were not reached at the time of analysis 
but the estimated 1-year PFS was 53% (95% confidence interval [CI], 37-66%) and 1-year OS 
was 81% (95% CI, 68-89%). In subgroup analysis, similar efficacy was observed in patients with 
either regional or distant metastatic disease involvement (43 vs. 49% response rate, respectively). 
Several trials are ongoing which utilize PD-1 antibodies in the HSCT setting. A study of the PD- 
1 inhibitor pembrolizumab as maintenance after autologous HSCT is enrolling in diffuse large B- 
cell lymphoma (DLBCL), classical HL, and T cell non-HL (NCT02362997). In addition, studies 
are enrolling using nivolumab after autologous HSCT in multiple myeloma (NCT03292263) and 
evaluating the PD-L1 antibody durvalumab for DLBCL (NCT03241017). PD-1 blockade has a 
track record of clinical benefit in post-HSCT patients: a report of 3 classical HL patients who 
relapsed after allo-HSCT all had objective responses to the PD-1 inhibitor nivolumab [20]. 
Haverkos and colleagues treated classical HL patients who relapsed after allo-HSCT with PD-1 
blockade as well and noted an overall response rate of 77% (15 complete and 8 partial responses 
among 30 patients) [14]. Herbaux and colleagues reported a 95% response rate with a 1-year PFS 
of 58% and 79% 1-year OS among 20 classical HL patients treated with nivolumab after relapse 
following allo-HSCT [13]. 
Anti-tumor response rates among post-renal allograft transplant patients with advanced 


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malignancies has not uniformly been reported – as the literature is comprised of cases reports 
and a few series. That said, complete and partial responses in this setting have been observed 
[21]. 
2.2.2 
Mechanistic target of rapamycin (mTOR) inhibition: Everolimus and Sirolimus 
 
2.2.2.1 
Mechanism of action and pharmacology 
 
Everolimus is a macrolide immunosuppressant and a mechanistic target of rapamycin (mTOR) 
inhibitor which has antiproliferative and antiangiogenic properties. It reduces protein synthesis 
and cell proliferation by binding to the FK binding protein-12 (FKBP-12), an intracellular 
protein, to form a complex that inhibits activation of mTOR (mechanistic target of rapamycin) 
serine-threonine kinase activity. It also reduces angiogenesis by inhibiting vascular endothelial 
growth factor (VEGF) and hypoxia-inducible factor (HIF-1) expression. 
 
Everolimus is rapidly absorbed with a volume of distribution of 128-589L and is 74% protein 
bound. The drug is extensively metabolized in the liver by CYP3A4 and yields six weak 
metabolites [22]. The tablet form is 30% bioavailable and this is reduced by 22% with a high- 
fate meal and by 32% with a light-fat meal. The tablet for suspension form has an area under the 
curve (AUC) equivalent to tablets although peak concentrations are 20-36% lower and steady 
state concentrations are similar [23]. Systemic exposure is reduced by 12% with a high-fat meal 
and 30% with a low-fat meal. The half-life of elimination is about 30 hours and the time to peak 
plasma concentration is about 1-2 hours. Fecal excretion is about 80% with around 5% urinary 
excretion [24]. 
 
Sirolimus inhibits T-lymphocyte activation and proliferation in response to antigenic and 
cytokine stimulation and inhibits antibody production. Its mechanism differs from other 
immunosuppressants. Sirolimus binds to FKBP-12, an intracellular protein, to form an 
immunosuppressive complex which inhibits the regulatory kinase, mTOR. This inhibition 
suppresses cytokine mediated T-cell proliferation, halting progression from the G1 to the S phase 
of the cell cycle. 
 
Sirolimus is rapidly absorbed with a volume of distribution of 12L/kg and is about 92% protein 
bound to albumin primarily. The drug is extensively metabolized in the intestinal wall via P- 
glycoprotein and hepatic CYP3A4 enzymes to seven major metabolites. The oral solution form is 
14% bioavailable where the oral tablet form is 27% higher relative to the oral solution 
bioavailability. Half-life of elimination is on average 62 hours (range: 46-78 hours) and extended 
up to 113 hours in those with hepatic impairment. Time to peak concentration is 1-3 hours for the 
oral solution and 1-6 hours for the oral tablet. Fecal excretion is about 91% due to the P- 
glycoprotein-mediated efflux into the gut lumen, and 2% urinary excretion [25]. 
 
2.2.2.2 
Clinical safety 
 
The dose and schedule of everolimus for clinical use was established in a study of 55 advanced 
solid tumor patients using a dose escalation scheme whereby dose limiting toxicity (DLT) of 
stomatitis, neutropenia, and hyperglycemia yielded a recommended 10 mg daily dose for further 


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development [24]. Everolimus has established safety in patients with advanced renal cell 
carcinoma (RCC) where a phase II study utilized a 10 mg daily oral dose without interruption 
with permitted dose modifications for toxicity among 39 patients. Common toxicities included: 
nausea (38% of patients), anorexia (38%), diarrhea (31%), stomatitis (31%), pneumonitis (31%), 
and skin rash (10%). Grade 3-4 adverse events included pneumonitis (18%) transaminase 
elevations (10%), thrombocytopenia, hyperglycemia, and alkaline phosphatase elevations (8% 
each), and hyperlipidemia (5%) [26]. In a phase III, randomized trial, everolimus and 
exemestane (endocrine hormone therapy) was compared in 724 post-menopausal hormone- 
receptor positive breast cancer patients with similar expected toxicities as noted in RCC. In 
addition, grade 3-4 adverse events included: stomatitis (8%), anemia (6%), dyspnea (4%), 
hyperglycemia (4%), fatigue (4%), and pneumonitis (3%) in the hormone and mTOR 
combination arm [27]. 
 
Outside of treatment for malignancy, mTOR inhibition also has an established role as 
immunosuppression alone or in combination for kidney transplant recipients to prevent organ 
rejection. In the multicenter, open-label ZEUS study of everolimus-based, calcineurin-inhibitor 
(CNI)-free immunosuppression for recipients of de-novo kidney transplants, 155 patients 
received an everolimus-based regimen based on trough concentrations (6-10 ng/mL) with a 
primary objective of showing favorable renal function at 1-year post-transplant [28]. In the 
mTOR inhibition arm, 76% (118 patients) completed therapy with rates of biopsy-proven acute 
renal rejection being around 10% (n = 15/154). Adverse events included elevated lipid 
concentrations, mildly elevated urine protein excretion, and lower hemoglobin concentrations in 
the everolimus-based arm. Thrombocytopenia, aphthous stomatitis, and diarrhea also were 
notable in the mTOR inhibition arm. Similarly, a multinational comparative, randomized trial 
using sirolimus 1-5 mg/day adjusted to a trough concentration of 8-15 ng/mL at the time of 
conversion to the agent (and 7-15 ng/mL thereafter) in 57 patients post-cardiac transplantation 
compared with a CNI was reported [29]. The most common adverse events in the sirolimus arm 
were diarrhea (28%), skin rash (28%), and infection (47%). Everolimus also has established 
immunosuppressive safety in pediatric transplant recipients: a phase I trial examined single dose 
everolimus in combination with cyclosporin A and steroids with and without azathioprine. 
Nineteen children enrolled at 1.2 mg/m2 per day which was safe and well tolerated. There was no 
increase in infection rates [23]. 
 
2.2.2.3 
Clinical efficacy 
 
Everolimus has demonstrated efficacy as immunosuppression following de-novo lung 
transplantation as noted in an investigator-sponsored, single institution study from Germany in 
2016 [30]. Forty-three patients were randomized to everolimus (over mycophenolate mofetil 
[MMF]) and the everolimus group had less rates of acute organ rejection, lower rates of 
cytomegalovirus (CMV) infection, and lower rates of respiratory tract infection. In addition, 
rates of bronchiolitis obliterans syndrome (BOS) were lower (1/43 patients) compared with the 
MMF group (p=0.04). There was a notable dropout rate in the mTOR inhibition group due to 
drug-related side effects, which are discussed above. Among de-novo kidney transplant 
recipients in the ZEUS trial, mTOR inhibition demonstrated somewhat higher rates of acute 
kidney rejection (10%) compared with 3% in the CNI group [28]. Sirolimus had numerically 
higher acute rejection rates compared with MMF in a post-cardiac transplant group, but overall 


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rates of rejection were low, comparatively [29]. 
2.2.3 
Combining Cemiplimab and mTOR inhibition 
 
2.2.3.1 
Preclinical efficacy 
 
While no data have yet reported the safety or efficacy of PD-1/L1 blockade used in combination 
with everolimus or mTOR inhibition, therapeutic efficacy in the early preclinical setting suggests 
that combining these agents could offer enhanced anti-tumor effect [31]. Hirayama and 
colleagues treated immunocompetent mice with RCC with anti-PD-L1 therapy and everolimus 
and showed a significant decrease in tumor burden as compared with anti-PD-L1 and placebo 
alone groups. They also noted increased tumor-infiltrating lymphocytes (TILs) and a higher ratio 
of CD8+ cytotoxic T cells compared to TILs in the combination arm. It is important to 
acknowledge that a serious and overlapping toxicity shared by both anti-PD-1/L1 and 
mTOR inhibitors is pneumonitis, and it is unknown whether combined use increases the 
likelihood of lung inflammation as compared with either agent alone. Nonetheless, we are 
excluding patients with significant renal dysfunction which have been associated with the 
highest risk of pneumonitis on mTOR inhibitors [32]. 
 
2.3 
Rationale 
 
Until 2018 there were no systemic therapies approved for the treatment of advanced or metastatic 
cSCC, despite its significant cosmetic and functional morbidity and overall poor prognosis. 
However, UV radiation leading to a rich mutational burden in this disease proved a promising 
attribute when considering the influx of novel immunotherapies in cancer medicine. Immune 
checkpoint inhibitors targeting PD-1 work to remove the inhibitory break signal on surrounding 
T cells to enhance tumor killing potential [33]. Cemiplimab, an anti-PD-1 antibody, 
demonstrated a nearly 50% durable response rate in advanced cSCC with a favorable toxicity 
profile – leading to regulatory approval of this agent for an otherwise devastating disease [10]. 
 
Despite the success of solid organ and hematopoietic stem cell transplantation (HSCT) in the last 
decade, transplant recipients remain at high-risk for second cancers given their altered immune 
systems and immunosuppressive needs [34] – with cSCC representing the most common new 
malignancy with a nearly 100-fold risk increase in this population [11]. When the cSCC becomes 
advanced or metastatic post-transplant, the treating physician is left with minimizing systemic 
immunosuppression or offering cytotoxic chemotherapy to palliate the disease. Of note, mTOR 
inhibitors (namely everolimus and sirolimus) are generally the preferred immunosuppressive 
agent after transplant to prevent future malignancies [35]. While immune checkpoint inhibitors 
have revolutionized the cancer landscape, trials have excluded this high-risk, but in-need 
population for fear of precipitating transplant rejection by stimulating a broad immune response 
– a scenario that has been reported of late [34, 36, 37]. In addition, including post-HSCT patients 
brings concern about the recrudescence of GVHD. Recent studies have shown that rates of acute 
GVHD exceed 45-50% when a patient is challenged with PD-1 blockade for relapse >3 months 
out from their prior HSCT and when they have a prior history of acute GVHD [13, 38]. While 
acute GVHD can occur in post-HSCT patients exposed to PD-1 blockade even in the absence of 
prior GVHD, a shorter time from HSCT increases the risk significantly – therefore we expect the 


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risk to be lower given the requirement that patients enrolled to this study be ≥2 years out from 
HSCT. 
While the hazards of immune checkpoint therapy in HSCT and renal transplant recipients is 
important to recognize, advanced cSCC patients post-transplant are often left with no further 
therapeutic options and the prospect of morbidity and death. It is not known whether response 
rates to PD-1 blockade are similar in prior transplant recipients with cSCC, moreover the actual 
rate of allograft rejection or GVHD has not been elucidated in this population. A uniform and 
aggressive approach to immunomodulation using dynamic immunosuppression (as not to impair 
the anti-tumor response) has not been applied to these patients to further understand the role of 
PD-1 blockade in this critical population. Barnett and colleagues reported the use of a dynamic 
immunosuppression regimen (combining pulsed steroids before, concurrent, and rapidly tapering 
after PD-1 blockade with mTOR inhibition) in a single patient with microsatellite unstable 
duodenal adenocarcinoma having undergone kidney transplantation and receiving nivolumab – 
with no evidence organ rejection nearly a year out from therapy [18]. Similarly, small series have 
demonstrated success with mTOR inhibition as the backbone of immunosuppression to prevent 
organ rejection when also a patient with concomitant immune checkpoint blockade [17, 21]. 
 
Here we plan to investigate PD-1 blockade with cemiplimab in post-allo-HSCT and post-renal 
allograft transplant populations to better understand anti-tumor activity and to potentially 
mitigate the risk of acute rejection by using a dynamic mTOR-based immunosuppression 
regimen in our renal transplant recipients. 
 
2.4 
Correlative Studies Background 
 
Clinical trial administration of immune checkpoint blockade among prior transplant recipients 
with a modified immunosuppressive regimen will provide a unique opportunity to understand 
immunology within this high-risk and vulnerable population. Peripheral blood and tumor tissue 
biopsy samples will be required before (at baseline) and after (after 30 days or 2 cycles of 
therapy) anti-PD-1 therapy, with an additional required tissue biopsy at the time of organ 
rejection or the development of GVHD to assess the off-target immunologic effects of treatment. 
 
Phenotypic analysis of immune cells in the blood and tumor microenvironment. Incubation of 
peripheral blood and tumor biopsy samples with monoclonal antibodies specific for different cell 
markers will be used to identify immune cell subsets and tumor cells. After incubation of cells 
with monoclonal antibodies, individual subsets are then enumerated by flow cytometry (and 
immunohistochemistry [IHC]/multiplexed immunofluorescence [MIF] where applicable). These 
studies will allow us to measure quantitative changes of individual cell populations that occur as 
a result of anti-PD-1 treatment. Mass cytometry (CyTOF) allows for high throughput analysis of 
single cells for a large number of parameters, and has recently been used to deeply 
immunophenotype and track the inhibitory and activating receptor diversity of human immune 
cells [39]. 
 
Plasma cytokines and chemokines. ELISA or other relevant assays will be used to measure levels 
of key cytokines (including IL-2, IFN-γ etc.), chemokines (such as CXCL2, CXCL5 etc.) and 
soluble ligands in plasma samples. 


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Functional assays. To assess the functional capacity of cytotoxic T cells that expand in vivo in 
response to treatment, selected samples will be used to assess their cytokine and cytotoxicity 
responses after re-stimulation with cytokines and tumor target cells. 
DNA analyses. Additional genetic analyses (e.g., short term tandem repeats [STRs]) will be 
considered to assess clearance of measurable disease and underlying tumor subclones and 
banked DNA and cell samples would be accessed for such analyses. 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 Patients must have histologically confirmed, advanced or metastatic cutaneous 
squamous cell carcinoma (cSCC) with 1 or more measurable lesions (greater than or 
equal to 1 cm). 
 
3.1.2 A history of either (Cohort 1) allogeneic hematopoietic stem cell transplant (allo- 
HSCT) and ≥ 2 years or 730 days from day 0 of their HSCT with adequate bone 
marrow function (see Section 3.1.6) and off of all systemic immunosuppression 
(topical agents permitted) for at least 3 months prior to enrollment; sequelae of 
chronic GVHD is permitted (i.e. chronic dry eyes, sclerodermatous skin changes, etc.) 
if the patient is not on systemic immunosuppression, or (Cohort 2) a renal transplant 
with a functioning allograft (at least 6 months from allograft transplant) as determined 
by estimated glomerular filtration (GFR) rate (CKD-EPI equation 1 [40], Appendix A) 
≥ 30 mL/min, baseline proteinuria lower than 0.5 g/day (spot urine protein-creatinine 
ratio), and off antiproliferative immunosuppressive medications. 
 
3.1.3 Willing to provide blood and tissue from diagnostic biopsies. 
3.1.4 Age 18 years or older. 
 
3.1.5 ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix B). 
 
3.1.6 Participants must have adequate organ and marrow function as defined below: 
 
− 
leukocytes 
≥ 2,200/mcL 
− 
absolute neutrophil count 
≥ 1,000/mcL 
− 
platelets 
≥ 90,000/mcL 
− 
total bilirubin 
within normal institutional limits (except in cases where 
Gilbert syndrome is known or suspected, where total bilirubin should be < 3 mg/dL) 
− 
AST(SGOT)/ALT(SGPT) 
≤ 2.5 × institutional upper limit of normal 
− 
creatinine  
≤ 1.5 × institutional upper limit of normal 
OR 
− 
estimated GFR 
≥ 30 mL/min/1.73 m2 for participants with creatinine levels above 


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institutional normal (CKD-EPI equation). 
− 
urine protein/creatinine ratio < 0.5 (equal to less than 500 mg of proteinuria per day) 
3.1.7 Ability to understand and the willingness to sign a written informed consent document. 
3.1.8 A prior history of acute GVHD that has resolved, or sequelae of chronic GVHD 
following allo-HSCT is permitted. Active acute GVHD patients are excluded. 
3.1.9 Women of childbearing potential (WOCBP) must agree to use at least 1 highly effective 
form of contraception (refer to Appendix C for examples). WOCBP should plan to use an 
adequate method to avoid pregnancy for up to 7 months (30 days plus the time required 
for cemiplimab to undergo five half-lives) after the last dose of investigational drug. 
“Women of childbearing potential (WOCBP)” is defined as any female who has 
experienced menarche, who has not undergone surgical sterilization (hysterectomy or 
bilateral oophorectomy), who is not postmenopausal, who is sexually active with a male 
partner. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 
in the absence of other biological or physiological causes. In addition, women under the 
age of 55 must have a documented serum follicle stimulating hormone (FSH) level less 
than 40 mIU/mL. 
3.1.10 Women of childbearing potential, as defined above, must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to the start of cemiplimab. 
3.1.11 Men who are sexually active with WOCBP must agree to use any contraceptive method 
with a failure rate of less than 1% per year. Men who are sexually active with WOCBP 
will be instructed to adhere to contraception for a period of 7 months after the last dose of 
investigational product. Women who are not of childbearing potential as defined above, 
and azoospermic men) do not require contraception. See Appendix C for further guidance 
on contraception. 
3.2 
Exclusion Criteria 
Participants who have had chemotherapy or radiotherapy within 1 week prior to entering 
the study or those who have unresolved toxicities from prior anti-cancer therapy more 
than 2 weeks earlier, defined as not resolved to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE, version 5.0), grade 0 or 1. 
 
3.2.1 Participants who are receiving any other investigational agents. 


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3.2.2 For Cohort 1 allo-HSCT patients enrolling to the study, corticosteroid doses > 10 mg 
of prednisone daily or equivalent within 4 weeks of the first dose of PD-1 inhibitor 
are prohibited. For Cohort 2 renal transplant patients enrolling to the study, 
corticosteroid use is permitted if used as part of their immunosuppressive regimen 
for graft protection prior to enrollment. 
 
3.2.3 Existing significant autoimmune conditions. Patients with a history of Hashimoto 
thyroiditis who are stable on replacement hormone therapy are not excluded. 
3.2.4 Known human immunodeficiency virus carrier or a diagnosis of immunodeficiency. Any 
positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, 
e.g., Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative). 
3.2.5 Kidney transplant recipients with active acute rejection. 
3.2.6 Allergy to cemiplimab or any of its components. 
3.2.7 Any prior exposure to the phosphoinositide 3-kinase inhibitor idelalisib. 
3.2.8 Subject who has been treated with immunotherapy. This includes prior treatment with 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways (including chimeric 
antigen receptor [CAR] T cell therapies). Prior topical or intralesional immunotherapies 
(e.g. imiquimod, talimogene laherperepvec) are allowed. 
3.2.9 Subject with known and untreated brain metastases should be excluded from this clinical 
trial because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other 
adverse events. However, baseline brain imaging is not required prior to enrollment in the 
study if patients are asymptomatic. Patients at least 4 weeks out from metastatic central 
nervous system (CNS) treatment are permitted to enroll, if they are asymptomatic, 
radiographically stable per the investigator, and on stable doses of anti-epileptic drugs 
(AEDs) and oral corticosteroids (for Cohort 1 only, the patient must be on 10 mg of 
prednisone daily equivalent dosing or less, see 3.2.2) at the time of enrollment. 
3.2.10 Participants receiving any medications or substances that are strong inhibitors or inducers 
of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is 
important 
to 
regularly 
consult 
a 
frequently-updated 
list 
such 
as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information. As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product. 


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3.2.11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. 
3.2.12 Known non-infectious pneumonitis or any history of interstitial lung disease. 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered. 
4.1 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed. 
 
 
5. TREATMENT PLAN 
 
While accrual is expected to be slow, we will approve two patients to enroll into to each cohort 
at a time to monitor toxicity appropriately. 
 
Eligibility and exclusion criteria are provided in Section 3. These criteria will be assessed within 
14 days prior to study registration to establish eligibility and baseline values. 
 
Informed consent will be obtained after the study has been fully explained to the subject and 
before the conduct of any screening procedures or assessments. 
 
Demographic information and baseline characteristics will be collected at the Screening Visit. 
Standard demographic parameters include age, sex, and race/ethnicity (recorded in accordance 
with prevailing regulations). Baseline characteristics will include ECOG PS (Appendix B), 


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disease status, and medical histories. 
5.1 
Treatment Regimen 
 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy during the course of treatment. 
Treatment cycles will be 21 days throughout the protocol. Patients are assigned to one of two 
predetermined Cohorts based on their prior transplant history: Cohort 1 (prior allogeneic 
hematopoietic stem cell transplant [allo-HSCT] history) or Cohort 2 (prior renal or kidney 
transplant history). 
 
5.1.1 
Cemiplimab Treatment (same for both Cohort 1 and Cohort 2) 
 
Cemiplimab (350 mg IV) will be administered in the outpatient setting at the beginning of the 
study (following a prednisone lead-in in Cohort 2 only) and will be dosed every 21 days (3 
weeks) until disease progression, intolerability, or limiting toxicity. 
 
5.1.2 
Dynamic Immunosuppression (Cohort 2 only) 
 
Patients in Cohort 2 with a history of prior renal transplant will need to transition to dynamic 
immunosuppression with either sirolimus or everolimus (mTOR inhibitors) during a lead-in 
phase of the study, 7-10 days prior to receiving the first dose of cemiplimab. If the patient is on 
an existing immunosuppression regimen that includes other agents (azathioprine, tacrolimus, 
MMF) they will need to be cross-tapered in discussion with the lead transplant nephrologist on 
the study team, Dr. Naoka Murakami. 
 
5.1.2.1 
mTOR inhibitor and Prednisone Lead-in 
 
Patients in Cohort 2 will start mTOR inhibition with either sirolimus or everolimus at least 7-10 
days prior to receiving the first dose of cemiplimab (Cycle 1, Day 1). The choice of agent, 
starting dose, and titration of mTOR dosing to optimal blood levels is at the discretion of the 
treating transplant nephrologist. 
 
Patients in Cohort 2 will also receive prednisone 40 mg orally the day prior to the start of 
cemiplimab dosing (Cycle 1, Day 1). 
 
5.1.2.2 
mTOR inhibitor and Prednisone dosing Scheme After Lead-in 
 
In Cohort 2, after the patient starts mTOR inhibition and receives 40 mg of prednisone as their 
lead-in to the first dose of cemiplimab, the patient then receives 40 mg of prednisone orally on 
the day of cemiplimab treatment (Cycle 1, Day 1) and for 2 days after cemiplimab dosing, 
followed by 20 mg daily for three additional days after anti-PD-1 dosing. Then on Cycle 1, Day 
7 the patient tapers to prednisone 10 mg orally daily and remains on this dose continuously until 
the day prior to the next cycle when the schedule repeats: 


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5.1.2.3 
Antibiotic prophylaxis on immunosuppression 
 
Prophylactic antimicrobial and antiviral use is permitted while patients are receiving mTOR 
inhibition and prednisone as part of dynamic immunosuppression. 
 
Dose adjustments of mTOR inhibitors based on trough levels throughout the study do not impact 
the timing or dosing schedule of cemiplimab in the absence of toxicity concerns. 
 
5.2 
Pre-Treatment Criteria 
 
5.2.1 
Cycle 1, Day 1 
 
Laboratory evaluations need to be repeated (except mTOR monitoring levels) and reviewed to 
re-meet eligibility criteria on Cycle 1, Day 1. In Cohort 2, patients must be on mTOR inhibition 
and have taken their 40 mg prednisone oral dose prior to cemiplimab on Cycle 1, Day 1. 
5.2.2 
Subsequent Cycles 
 
Reasonable effort should be made to conduct study visits on the day scheduled ( 3 days). 
Laboratory evaluations should be reviewed prior to the start of each cycle. 
 
Any changes from screening clinical evaluation findings that meet the definition of an adverse 
event (AE) will be recorded on the AE page of the eCRF. The drug diary for the prior cycle 
should be reviewed at each study visit by the clinical staff. 
 
5.3 
Agent Administration 
 
5.3.1 
Cemiplimab 
 
No pre-medications are recommended prior to the administration of cemiplimab. Day -1 
prednisone is part of dynamic immunosuppression, not pre-medication. 
Cemiplimab (350 mg flat dose IV every 21 days) will be administered in an outpatient setting as 
an approximately 30-minute infusion (+/- 20 minutes). Post-treatment observation is required for 
30-minutes after the first infusion only to monitor for immune-mediated infusion reactions. 
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5.3.2 
Dynamic Immunosuppression (Cohort 2) 
 
Participants in Cohort 2 will receive everolimus or sirolimus and prednisone on an outpatient 
basis. Everolimus or sirolimus pills can be taken with or without food as prescribed based on 
desired dosing (although ingestion of a high-fat meal should be avoided with sirolimus). As 
noted below in Section 5.4.2, grapefruit juice should be avoided. Dosing of mTOR inhibitors is 
often once or twice daily (aiming for approximately 10-12 hours between doses) and the patient 
should try to be consistent with dose administration timing. Prednisone dosing daily should also 
be timed so as to maintain consistent time intervals between daily doses. 
 
Immunosuppression compliance will be monitored as part of the study. Each participant will be 
required to maintain a medication diary of each dose of immunosuppressive medication. The 
medication diary will be returned to the clinic study staff at the end of each 21-day cycle. 
 
If a dose of immunosuppression is missed by  6 hours from the last oral dose, then the next dose 
should be retimed for the morning of the following day. Any dose of immunosuppression that 
was missed less than 6 hours from the last administration should be taken, and the following 
dose retimed for the morning of the following day. If immunosuppression is not tolerated, or 
vomiting results in loss of the ingested dose, the dose should be skipped, and the next planned 
dose attempted when possible. The immunosuppressive drugs may be crushed, chewed, or 
dissolved if necessary (everolimus is also available in a liquid suspension preparation). 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1 
Concomitant Medical Guidelines 
 
Pertinent concomitant medications will be recorded on the case report form (CRF). If changes 
occur during the trial period, documentation of drug dosage, frequency, route, and date may also 
be included on the CRF. 
 
Topical, intradermal, and intraarticular corticosteroids are permitted. 
 
5.4.2 
CYP3A4 Interactions among mTOR inhibitors 
 
mTOR inhibitors are a known substrate of CYP3A4 and P-glycoprotein/ABCB1 and therefore 
medications which can cause drug-drug interactions are listed in the Table below. Strong 
inducers of CYP3A4 are identified below with monitoring during concomitant therapy 
recommended. Category X drugs below should be avoided. 
 
Strong 
CYP3A4 
inducers 
Angiotensin- 
converting enzyme 
inhibitors (ACEI) 
Clotrimazole 
(topical)* 
Clozapine 
Flibanserin 
Antidiabetic 
agents 
Deferasirox 
CYP3A4 
inducers 
Fosaprepitant 
Aripiprazole 
Efavirenz 
CYP3A4 
inhibitors 
Nimodipine 
Bosenten 
Erythromycin 
Denosumab 
P-glycoprotein 
Chloramphenicol 
Fluconazole* 
Dofetilide 
Ranolazine 
Clofazimine 
Micafungin* 
Echinacea 
Roflumilast 


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Rifampin 
Rifabutin 
Phenobarbital 
inhibitors 
Carbamezapine 
Phenytoin 
Risk X 
Antihepaciviral 
combination 
products 
Conivaptan 
Cyclosporine 
Grapefruit juice 
St. John’s Wort 
Voriconazole 
* azole antifungal agents may cause an increase in serum concentration of sirolimus only 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until any of the following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s), see Section 6.1.3 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• 
Participant decides to withdraw from the protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
• 
Pregnancy 
 
The reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. When a participant is removed from protocol therapy and/or is off study, 
participant’s status must be updated in OnCore in accordance with REGIST-OP-1. 
 
Following completion of 2 years or 24 months of protocol therapy with cemiplimab, the patient 
can be moved to commercial product at the discretion of the treating physician. 
 
5.6 
Duration of Follow-Up 
 
Participants will be followed for best overall response and development and documentation of 
first disease progression and for survival throughout the course of the trial for 1 years from the 
time of end of treatment visit Participants who are removed from protocol therapy for an 
unacceptable adverse event and who have not developed first disease progression at time of 
discontinuation of protocol therapy will continue to be followed for 1 year from EOT visit. 
Follow-up after discontinuation of the cemiplimab study treatment should include one 30-day 
follow up visit, then routine check-ins every 3-4 months up to 12 months (1 year), which can 
overlap with routine clinic visits or include telephone encounters. Participants removed from 
protocol therapy for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event. 
 
 
5.7 
Criteria for Taking a Participant Off Study 


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Participants will be removed from study when any of the following criteria apply: 
• 
Lost to follow-up 
• 
Withdrawal of consent for data submission 
• 
Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. In addition, the study team will ensure the participant’s status is updated in OnCore 
in accordance with REGIST-OP-1. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator, Glenn J. Hanna, MD, call Partners paging 
directory at (617) 732-5500 and ask for pager #46231. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated below. The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP website: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
6.1 
Cemiplimab 
 
There will be no dose reductions for cemiplimab permitted. Doses of cemiplimab may be 
interrupted, delayed, or discontinued depending on how well the participant tolerates the 
treatment. Cemiplimab dosing visits are not skipped, only delayed. If cemiplimab doses are 
delayed or skipped, study testing resumes when the next cycle of cemiplimab begins and drug is 
resumed. However, immunosuppression dosing continues during the delay or skipped periods. 
6.1.1 
Cemiplimab Dose Delays or Holds 
 
Administration of cemiplimab should be delayed and the dose held for the following adverse 
events: 
• 
Grade II, III, or IV acute GVHD according to the modified Glucksberg scale (see Section 
7.7) in Cohort 1 
• 
Moderate to severe chronic GVHD by the revised NIH consensus scoring system (see 
Section 7.8) in Cohort 1 
• 
Grade 2 non-skin, drug-related adverse event (AE), with the exception of fatigue 
• 
Grade 2 drug-related creatinine, AST, ALT and/or total bilirubin abnormalities unless 
specifically due to chronic GVHD and not meeting stopping criteria in bullet two above 
• 
Grade 3 skin, drug-related adverse event 
• 
Grade 3 drug-related laboratory abnormality, with the following exceptions: lymphopenia 
or asymptomatic amylase or lipase does not require dose delay 


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• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the investigator, warrants delaying the dose of study medication. 
Note: see Cemiplimab investigator brochure and guidelines on managing immune-related 
toxicities (Appendix E) 
6.1.2 
Re-treatment Criteria for Cemiplimab 
 
Participants who require delay of cemiplimab should be re-evaluated weekly or more frequently 
if clinically indicated and resume dosing when re-treatment criteria (as described below) are met. 
Participants with a delay in dosing beyond 12 weeks should be considered for discontinuation of 
protocol treatment and discussed with the Overall PI. 
 
Subsequent dosing may be re-started if subjects continue to meet laboratory criteria (eligibility 
criteria values). The investigator will determine if subsequent dosing is appropriate for subjects 
who have laboratory or clinical abnormalities that do not meet dose discontinuation criteria. 
 
Immune-mediated adverse events or acute/chronic GVHD episodes or flares managed with oral 
steroid doses or standard treatment need (1) to resolve to Grade I for acute GVHD within 10 
days of starting GVHD treatment, (2) to mild NIH consensus score for chronic GVHD, or (3) to 
grade 1 AE symptoms or less for immune-related AEs, and the patient needs to be on ≤ 10 mg 
prednisone daily equivalent dose before resuming cemiplimab on study. 
 
All related grade 3+ toxicities and cases of acute or chronic GVHD should be discussed with the 
Overall PI, prior to subsequent dosing. 
 
6.1.3 
Cemiplimab Discontinuation 
 
Administration of cemiplimab should be discontinued for the following AEs: 
• 
Unresolved Grade II, III, or IV acute GVHD according to the modified Glucksberg scale 
despite 14 days (or 2 weeks) of systemic corticosteroids (see Section 7.6.1) in Cohort 1 
• 
Any degree of biopsy proven acute renal allograft rejection (see Section 7.6.3) in Cohort 
2 
• 
A grade 3 pneumonitis and grade 3 uveitis will require permanent discontinuation. 
• 
A recurrent grade 3 immune-mediated adverse reactions, grade 2 or 3 immune-mediated 
adverse reactions persistent for 12 weeks or longer, and any grade 3+ infusion-related 
immune reaction. 
• 
Any grade 4 treatment-related adverse event will require permanent discontinuation with 
the following exceptions: 
− Certain grade 4 electrolyte abnormalities (specifically hypo/hypercalcemia, 
hypo/hyperchloremia, hypo/hypermagnesemia, hypo/hyperphosphatemia) that < 72 
hours in duration 
− Grade 4 neutropenia < 5 days in duration 
− Grade 4 increase in amylase or lipase that is not associated with clinical or 
radiographic evidence of pancreatitis 
− Grade 4 lymphopenia < 5 days in duration 


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The consideration to re-initiate study therapy under these exceptions will be made on a case by 
case basis after considering the overall benefit/risk profile and in consultation with the Overall 
PI. 
6.2 
Dynamic Immunosuppression 
 
Dose delays of prednisone and mTOR inhibition are discouraged as to promote immune 
tolerance of the bone marrow and kidney organ graft while the patient is receiving immune 
checkpoint blockade with cemiplimab. 
 
Dose modifications for prednisone may be required outside of the planned treatment dosing 
outlined above if the patient has immune-mediated AEs or graft rejection issues that require a 
change in dosing. Prednisone adjustments will be made by the treating investigator at their 
discretion. 
 
Everolimus or sirolumus dosing will be determined by target trough levels obtained or drawn every 7-10 
days (± 3 days) in cycles 1-2, then on days 1, 8 for cycles 3-6, and on day 1 only for cycle 7 onward while 
on the study. There is delay in outside reporting of mTOR drug levels and this must be accounted 
for with periodic monitoring. The involved transplant nephrologist participating in the patient’s 
care should determine the dose and schedule of mTOR inhibition based on a target trough level 
of 4-6 ng/mL for everolimus or sirolimus. 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
All adverse events experienced by participants will be collected during screening, from the time 
of the first dose of cemiplimab study treatment, through the study and within 30 days of the last 
study intervention. Participants continuing to experience toxicity at the last scheduled study visit 
may be kept on the study until the toxicity has resolved, or until the toxicity is deemed 
irreversible. 
 
7.1 
Expected toxicities or adverse events are those that have been previously identified 
as resulting from administration of cemiplimab. For the purposes of this study, an adverse event 
is considered expected when it appears in the current adverse event list in the investigator 
brochure or is included in the informed consent document as a potential risk. Most common 
adverse events or expected toxicities are listed below. Management of expected immune-related 
toxicities is described in Appendix E. 
Toxicities related to mTOR inhibitors and prednisone will be managed according to their 
respective package insert. 


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7.1.1 Adverse Events List 
7.1.1.1 
Adverse Event List(s) for cemiplimab 
The most common adverse reactions (> 10%) related to cemiplimab alone are: diarrhea, fatigue, 
nausea, constipation, rash, cough, decreased appetite, pruritis, and headache [10]. It is important 
to distinguish common immune-related AEs from cemiplimab with manifestations of acute or 
chronic GVHD (in Cohort 1) and possible acute renal allograft rejection (in Cohort 2). 
 
 
 
 
7.1.1.2 
Adverse Event List(s) for mTOR inhibitors, Everolimus and Sirolimus 
7.1.1.2.1. 
Everolimus 
Stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever 
asthenia, cough, headache, and decreased appetite. 
Please see package insert for a comprehensive list of adverse events. 
7.1.1.2.2. 
Sirolimus 
Peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, 
creatinine increased, abdominal pain, diarrhea, headache, fever, urinary tract infection, 
anemia, nausea, arthralgia, pain, and thrombocytopenia. 
Please see package insert for a comprehensive list of adverse events. 
7.1.1.3 
Adverse Event List for Prednisone 
Fluid retention, alteration in glucose intolerance, elevation in blood pressure, 
behavioral and mood changes, increased appetite and weight gain. 
Please see package insert for a comprehensive list of adverse events. 
 
7.2 Adverse Event Characteristics 
An adverse event (AE) is any undesirable sign, symptom or medical condition, or experience that 
develops or worsens in severity after starting the first dose of study treatment (cemiplimab) 
specified in the protocol, even if the event is not considered to be related to the study. 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 


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CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
• 
For expedited reporting purposes only: 
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol- 
Specific Expedited Adverse Event Reporting Exclusions. 
 
 
 
Attribution of the AE: 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is doubtfully related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.3 
Adverse Event Reporting 
 
7.3.1 
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI 
7.3.2 
Investigators must report to the Overall PI any adverse event (AE) that occurs after 
the initial dose of study treatment, during treatment, or within 90 days of the last dose 
of cemiplimab treatment on the local institutional SAE form. 
 
7.3.3 
DF/HCC Adverse Event Reporting Guidelines 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. 
Serious Adverse Events 
 
Definition of SAEs 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 


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• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [e.g. 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.) 
• 
Suspected transmission of an infectious agent (e.g. pathogenic or nonpathogenic) via the 
study drug is an SAE. 
 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (e.g. death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
 
 
 
7.3.4 Protocol-Specific Adverse Event Reporting Exclusions 
 
There are no protocol-specific adverse event reporting exclusions for this protocol. 
 
7.4 
Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. Submit by fax to 1-800-FDA-0178. 
 
7.5 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy. 
7.6 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
7.7 
Routine Adverse Event Reporting to Regeneron 
 
Routine Adverse Events will not be reported to Regeneron. Regeneron will be collecting SAE 


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reports only. 
All SAEs, whether related or not related to study drug, must be collected, including those 
thought to be associated with protocol-specified procedures. All SAEs must be collected that 
occur within 90 days of discontinuation of cemiplimab dosing. All SAEs should be followed to 
resolution or stabilization. 
All SAEs must be collected that occur during the screening period. If applicable, SAEs must be 
collected that relate to any protocol-specified procedure (e.g., a follow-up skin biopsy). The 
sponsor-investigator should report any SAE that occurs after these time periods that is believed 
to be related to study drug or protocol-specified procedure. 
The sponsor-investigator will reconcile the clinical database SAE cases (case level only) 
transmitted to Regeneron, but all SAEs must be reported to Regeneron within 24 hours of 
occurrence, and sent to medical.safety@regeneron.com. 
 
 
Serious Adverse Events 
 
Definition of SAEs 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [e.g. 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.) 
• 
Suspected transmission of an infectious agent (e.g. pathogenic or nonpathogenic) via the 
study drug is an SAE. 
 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (e.g. death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 


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Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
following the subject’s written consent, during treatment, or within 90 days of the last dose of 
treatment on the local institutional SAE form. 
Investigators will report AEs directly to the DFCI Office for Human Research Studies (OHRS) 
per the DFCI IRB reporting policy, using the local institutional SAE form. 
 
 
 
 
 
7.6.1 Acute GVHD Adverse Event Grading (Cohort 1) 
Symptoms of acute GVHD among Cohort 1 require staging at initial and subsequent visits to 
ensure accuracy of severity. The National Institutes of Health (NIH) consensus criteria use of 
clinical findings [41], rather than a set of time periods, defines acute vs. chronic GVHD for the 
purpose of this study. 
The modified Glucksberg grade (I-IV) should be utilized for on-study documentation (Table 
below). 
 
 
7.6.2 Diagnostic Criteria for Chronic GVHD (Cohort 1) 
 
Symptoms of chronic GVHD among Cohort 1 require staging at initial and subsequent visits to 
ensure accuracy of severity. The National Institutes of Health (NIH) consensus criteria use of 
clinical findings as summarized in the Table below [42], rather than a set of time periods, defines 
acute vs. chronic GVHD for the purposes of this study. 


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Organ/Site 
Diagnostic (sufficient alone for the 
diagnosis of chronic GVHD) 
Distinctive (see in chronic GVHD, but insufficient 
alone for the diagnosis) 
Skin 
Poikiloderma 
Lichen planus-like features 
Sclerotic features 
Morphea-like features 
Lichen sclerosis-like features 
Depigmentation 
Nails 
Dystrophy 
Longitudinal ridging, splitting, or brittle features 
Onycholysis 
Pterygium unguis 
Nail loss (usually symmetric; affects most nails)* 
Scalp and body hair 
New onset of scarring or nonscarring scalp alopecia 
(after recovery from chemoradiotherapy) 
Scaling, papulosquamous lesions 
Mouth 
Lichen-type features 
Hyperkeratotic plaques 
Restriction of mouth opening from sclerosis 
Xerostomia 
Mucocele 
Mucosal atrophy 
Pseudomembranes* 
Ulcers* 
Eyes 
New-onset dry, gritty, or painful eyes¶ 
Cicatricial conjunctivitis 
Keratoconjunctivitis sicca¶ 
Confluent areas of punctate keratopathy 
Genitalia 
Lichen planus-like features 
Vaginal scarring or stenosis 
Erosions* 
Fissures* 
Ulcers* 
GI tract 
Esophageal web 
Strictures or stenosis in the upper to mid 
third of the esophagus* 
Lung 
Bronchiolitis obliterans diagnosed with lung 
biopsy 
Bronchiolitis obliterans diagnosed with PFTs and 
radiology¶ 
Muscles, fascia, 
joints 
Fasciitis 
Joint stiffness or contractures secondary to 
sclerosis 
Myositis or polymyositis¶ 
* In all cases, infection, drug effects, malignancy, or other causes must be excluded. 
¶ Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes). 
PFTs = pulmonary function tests 
 
The NIH GVHD scoring system includes information on the number of organs or sites involved 
and the severity within each affected organ (e.g., skin, mouth, eyes, gastrointestinal tract, liver, 
lungs, joints/fascia, and genital tract) (see Form in Appendix F). Organ specific severity is scored 
from 0 to 3 with higher scores reflecting more severe disease. Based upon this information, the 
overall severity is scored as mild, moderate, or severe: 
• 
Mild – Involves two or fewer organs/sites with no clinically significant functional 
impairment 
• 
Moderate – Involves three or more organs/sites with no clinically significant functional 
impairment or at least one organ/site with clinically significant functional impairment, 
but no major disability 
• 
Severe – Major disability caused by chronic GVHD 
 
7.6.3 Suspected Acute renal allograft rejection (Cohort 2) 
 
For the purposes of this study, acute renal allograft rejection should be suspected in patients with 
one or more of the following: 


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• 
New increase in serum creatinine of ≥ 25% from baseline which is persistent for at least 7 
days or a serum creatinine that is higher than expected (such as in recently transplanted 
patients whose serum creatinine stops decreasing earlier than expected after 
transplantation). 
• 
Worsening hypertension 
• 
Proteinuria >1 g/day 
• 
Plasma donor-derived cell-free DNA (dd-cfDNA) >1% 
 
Any participant in Cohort 2 with suspected acute renal allograft rejection would require a renal 
allograft biopsy at the discretion of the involved transplant nephrologist to make the 
diagnosis, accurately grade the severity of rejection, and determine the degree of irreversible 
kidney damage. Biopsy of the renal allograft can also reveal other causes of renal inflammation 
and injury, including: cytomegalovirus (CMV) disease, BK (polyomavirus) nephropathy, 
interstitial nephritis, pyelonephritis, de novo or recurrent glomerular disease, and posttransplant 
lymphoproliferative disease (PTLD). 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7. 
 
8.1 
Cemiplimab 
 
8.1.1 
Description 
 
Cemiplimab is a covalent heterotetramer consisting of two disulfide-link human heavy chains, 
each of which is covalently bonded through disulfide linkages to a human kappa light chain. The 
antibody possesses an approximate molecular weight of 143.6 kilounified atomic mass unit 
(kDa) based on the primary sequence. There is a sing N-linked glycosylation site on each heavy 
chain, located within the constant region in the Fc portion of the molecule. The cemiplimab 
heavy chain possesses an IgG4 isotype constant region. The variable domains of the heavy and 
light chains combine to form PD-1 binding site within the antibody. 
 
Cemiplimab-rwlc (REGN-8210 or Libtayo®) is a recombinant human IgG4 monoclonal 
antibody that inhibits programmed death-1 (PD-1) activity by binding to PD-1 and blocking the 
interactions with the ligands PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of 
immune response, including anti-tumor response. PD-1 ligand upregulation may occur in some 
tumors and signaling through this pathway can contribute to inhibition of active T-cell immune 
surveillance of tumors. Blocking PD-1 activity has resulted in decreased tumor growth. 
Distribution: Vd: 5.3L, half-life elimination: 19 days, excretion: first dose clearance: 0.32 L/day, 
steady state: 0.21 L/day. 
 
8.1.2 
Form 
Solution, Intravenous [preservative free]: Libtayo®: 350 mg/7 mL (7 mL) [contains polysorbate 
80]. Clear to opalescent colorless to pale yellow liquid. May contain particles. 


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8.1.3 
Storage and Stability 
 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety 
measures for preparation and handling of cemiplimab include laboratory coats and gloves. 
 
8.1.4 
Compatibility 
 
Do not administer with other medications. Flush with NS or D5W at the end of infusion. 
 
8.1.5 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
 
8.1.6 
Preparation 
 
Cemiplimab-rwlc can be prepared per the package insert which can be referenced at: 
https://www.regeneron.com/sites/default/files/Libtayo_FPI.pdf 
 
8.1.7 
Availability 
 
Free of cost, investigational supply of cemiplimab, will be provided by Regeneron 
pharmaceuticals. 
 
8.1.8 
Ordering 
 
Dana-Farber Research Pharmacy and all pharmacies at all participating sites will request supply 
of cemiplimab, directly from Regeneron, by submitting an order form, provided by Regeneron. 
 
8.1.9 
Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form. (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage). 
 
8.1.10 Destruction and Return 
 
Unused supplies and expired supplies of the investigational agents will be destroyed on site, by 
the pharmacy, per institutional standard operating procedures. 
8.2 
Other Agents 
Everolimus or sirolimus (mTOR inhibitors) and prednisone will be stored and prepared per 


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standard of care/institutional guidelines. Everolimus or sirolimus (mTOR inhibitors) and 
prednisone will be obtained per standard of care clinical supply. 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
Correlative studies are planned as part of this study in order to characterize the peripheral and 
tumor immune microenvironment and perform tumor immunophenotyping and functional assays. 
A peripheral blood sample and fresh tissue tumor biopsy (B1) is required as part of enrollment to 
the study and after (30 days or 2 cycles of therapy but before cycle 3, [B2]) anti-PD-1 therapy. 
Blood and tissue will be sent for tumor immune profiling and other studies, which will include 
genomic and mutational analysis. Fine needle aspiration cytology samples alone are discouraged, 
but acceptable if no core material is available. 
 
An additional required tissue biopsy (B3R) is required at the time of organ rejection or the 
development of GVHD to assess the off-target immunologic effects of treatment. 
 
9.1.1 
Specimen Collection and Handling 
 
The study aims for 2-3 cores per mandatory tumor biopsy obtained throughout the study. The 
tumor biopsy may be core, a fine needle aspiration (FNA), or skin biopsy. If doing a skin core, 
any size up to 6mm is acceptable. 
• 
1 core is fresh tissue placed in RPMI containing 10% fetal bovine serum (FBS) 5 mL 
microcentrifuge tube for multiparametric flow cytometry or CyTOF, or other genomic or 
molecular studies. The tissue will and delivered to the Belfer Center for Applied Cancer 
Science, 360 Longwood Avenue, Boston, MA 02215, phone: 207-423-0958 or 631-487- 
6573 (contact: Patrick Lizotte, Ph.D.). The specimen must arrive in a timely fashion to 
facilitate processing for evaluation of immune cells. 
• 
1 or 2 cores are fixed or placed a standard specimen cup containing 10% neutral buffered 
formalin for IHC/MIF, genomic, and functional assay work. Once prepared, aliquoted 
core material for will be delivered immediately to the laboratory of Dr. Ravindra 
Uppaluri at the DFCI [Dana Building, 8th floor, room 819, 450 Brookline Avenue, 
Boston, MA 02215, phone: 617-632-3091]. 
 
The study aims to collect mandatory peripheral blood samples throughout the study. 
 
• 
4 tubes drawn in phlebotomy or clinic and captured in 8 mL whole blood, purple top 
tubes are collected at each time point for peripheral immunophenotyping. The volume of 
blood to be collected per blood draw for study purposes will not exceed 40 mL. After 
collection, two blood tube samples should be delivered immediately to the Belfer Center 
for Applied Cancer Science, 360 Longwood Avenue, Boston, MA 02215, phone: 207- 
423-0958 or 631-487-6573 (contact: Patrick Lizotte, Ph.D.). The other two samples 
should be delivered immediately to the Transplant Research Center, 221 Longwood 
Avenue, Boston, MA 02215, phone: 617-732-5252 (contact: Naoka Murakami, MD 


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PhD). The specimens must arrive in a timely fashion (ideally within 4 hours of 
colelction) to facilitate processing for evaluation of immune cells. 
The study aims to collect mandatory urine samples throughout the study for the detection of 
potential biomarkers of kidney rejection. 
• 1 urine cup (at least 10 mL) should be collected in clinic and after collection, the urine 
sample should be delivered immediately to the Transplant Research Center, 221 
Longwood Avenue, Boston, MA 02215, phone: 617-732-5252 (contact: Naoka 
Murakami, MD PhD). The specimen must arrive within 4 hours of collection to facilitate 
processing for evaluation of immune cells. 
All specimens will be de-identified and labeled with the participant’s study ID number, the date 
of acquisition, and timepoint on study [B1, B2, B3R as above]. Leftover specimens may be 
banked for future use and would be accessible to Dr. Glenn Hanna, the overall PI. 
 
9.1.2 
Planned Correlative Studies 
 
Peripheral blood and tumor biopsy samples will be treated with monoclonal antibodies specific 
for different immune cell markers (CD3, CD8, PD-1/L1, TIM-3, LAG-3, CTLA-4, FOXp3, 
CD56, etc.) to identify immune cell subsets (or phenotypes) and tumor cells. After incubation of 
cells with monoclonal antibodies, individual subsets are then enumerated by flow cytometry. 
These studies will allow us to measure quantitative changes of individual cell populations that 
occur as a result of anti-PD-1 treatment. Mass cytometry (CyTOF) will permit high throughput 
analysis of single cells for a large number of parameters, to deeply immunophenotype and track 
the inhibitory and activating receptor diversity of immune cells among samples. 
 
IHC/MIF is additionally planned on tumor biopsy specimens to identify immune cell population 
geographic and spatial interactions not depicted by flow cytometry or CyTOF. Antibody staining 
for immune cell markers noted above will be employed for slide overlay comparison among 
matched pre- and post-immunotherapy tumor biopsies (when available). 
 
Paired tumor biopsy material is also partitioned to perform whole-exome sequencing analyses on 
DNA, bulk RNA, or both (as tissue and resources permit). Additional T cell receptor (TCR) 
sequencing may also be explored. Mutational burden and individual alterations will be correlated 
with response. 
 
Peripheral blood and urine samples will be used for immune cell characterization with above 
flow cytometry, and matched to tumor samples to compare immune subsets in circulation with 
those in the tumor microenvironment. In addition, plasma and urine cytokine profiling will be 
employed to measure key inflammatory cytokines (IL-2, IFN-γ) to correlate with response. 
 
10. STUDY CALENDAR 
 
Baseline or screening evaluations are to be conducted within 2 weeks (14 days, ± 3 days) of the 
start of protocol therapy (either cemiplimab in Cohort 1, or the lead-in phase for Cohort 2). 


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Baseline imaging must be done < 3 weeks (21 days, ± 5 days) prior to the start of therapy. In the 
event that the participant’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. 
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted. 


 
 
ScreeningQ 
Lead-in 
Phase 
C1-2 3 
C3-6 3 
C7+ 3 
End of 
Treatment 
Visit 
+/- 3 days 
Follow-upR 
30 day f/u visit then 
Q 3-4 months up to 1 
year 
+/- 7 days 
EDC Timepoints 
D1 +/- 
3 days 
(window 
for cycle 
2 only) 
D8 
+/- 3 
days 
D15 
+/- 3 
days 
D1 
+/- 3 
days 
D8 
+/- 3 
days 
D1 
+/- 3 
days 
mTOR inhibitor 
(Everolimus or 
Sirolimus)A,2 
X2 
X2  
 
N/A 
PrednisoneB,2 
X2 
X2  
 
N/A 
Cemiplimab 
X 
X 
X 
Day 1 of every Cycle 
Informed consent 
X 
N/A 
Demographics 
X 
Screening 
Medical history 
X 
X 
X 
X 
X 
X 
Screening 
Concurrent medsC 
X 
X 
X 
X 
X 
N/A 
Physical exam 
X 
X 
X 
X 
X 
Screening 
Vital signs 
X 
X 
X 
X 
X 
Screening 
Height 
X 
Screening 
Weight 
X 
X 
X 
X 
X 
Screening 
Performance statusD 
X 
X 
X 
X 
X 
Screening, D1 of every Cycle, EOT 
Hematology labsE 
X 
X 
X 
X 
X 
Screening, D1 of every Cycle, EOT 
BUN/creatinine 
X 
X 
X2 
X2 
X 
X2 
X 
X 
Screening, Days 1, 8 and 15 for Cycles 
1&2, Day 1 for Cycles 7+, EOT 
UrinalysisF, 2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Screening, Day 1 of Cycles 1-7+, EOT 
Spot urine 
protein/creatinine 
ratioG,2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Screening, Day 1 of Cycles 1-7+, EOT 
Other ChemistriesH 
X 
X 
X2 
X2 
X 
X 
X 
Screening, Day 1 of Cycles 1-7+, EOT 
Urine or serum HCGI 
X 
XI 
N/A 
HIV, CMV, hepatitis 
panelJ,1,2 
X 
Screening 
HTLV1 
X1 
Screening 
BK virus1 
X1 
Screening 
mTOR blood levelsK,2 
X2 
X2 
 
N/A 
ECG 
X 
Screening 
Tumor assessmentsL 
XL 
XL 
 
Screening, Day 1 of Cycles 1-7+, EOT 
Mandatory Tumor or 
tissue biopsyM 
X 
XM 
XM 
Screening, Cycle 2 Day 15 
Mandatory Research 
bloodN 
X 
X 
X 
X 
X 
X 
Screening, lead in phase, Day 1 of 
Cycles 1-7+, EOT 
Mandatory Research 
X 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Screening, Every visit of Cycles 1-7+, 
 
 
 
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urineS,2 
EOT 
AE evaluationO 
X 
X 
X 
X 
X 
Screening, lead in phase, Day 1 of 
Cycles 1-7+, EOT 
Acute/Chronic GVHD 
scoringP,1 
X1 
X1 
X1 
X1 
X1 
Day 1 of all cycles, EOT, Follow up 
1 items marked with a #1 are only required for Cohort 1 (post-allo-HSCT patients) 
2 items marked with a #2 are only required for Cohort 2 (post-renal transplant patients) 
3 Cycles are 21 days in length. 
A either everolimus or sirolimus at the discretion of the treating transplant nephrologist 
B dynamic dosing scheme based on timing of PD-1 blockade: 40 mg the day before D1 of each cycle, 40 mg on D1 of each cycle through D3, then 20 mg D4 through D6 followed 
by 10 mg on D7-20 of each cycle until the day prior to the next cycle when the schedule of dosing repeats back to 40 mg, and so on 
C see prohibited concurrent medications and CYP3A4 interaction table in Section 5.4.2. 
D using ECOG performance status scale in Appendix B 
E hematology panel should include: CBC with differential, hemoglobin, hematocrit, platelets, absolute neutrophil count 
F urinalysis without a reflex culture required in Cohort 2 only 
G spot protein-creatinine ratio calculation required in Cohort 2 only 
H Chemistry panel should include: comprehensive metabolic panel, magnesium, phosphorus, LDH, and thyroid function testing (TSH, free T4). Only a BMP is required on D8 and 
D15 of cycles 1 and 2 in Cohort 2 
I Urine HCG testing: women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to the start of cemiplimab 
J HIV-1/2 antibody, CMV serologies (IgG/IgM), and hepatitis panel should include: HAV antibody, HbsAg, HbcAb, HbsAb, HCV antibody 
K everolimus or sirolimus trough levels should be drawn in the morning before the patient’s AM dose and the goal range is 4-6 ng/mL (reporting is delayed due to send out testing). 
Testing intervals are every 7-10 days (± 3 days) in cycles 1-2, then on days 1, 8 for cycles 3-6, and on day 1 only for cycle 7 onward. The treating transplant nephrologist will 
determine any dose changes based on trough levels while on study. 
L radiographic imaging with CT scans of the chest, abdomen and pelvis are required at screening (baseline imaging must be done ≤ 3 weeks [21 days, ± 5 days] prior to the start of 
therapy), and every 8 weeks [± 5 days] on study through cycle 10 at which point restaging scans can occur every 12 weeks [± 5 days]. CT neck with contrast should be included at 
each scan time point if clinical evidence of or concern for involved cervical neck disease. A PET-CT from scalp to toe can be used in lieu of CT imaging for some patients if 
clinically indicated 
M fresh tissue tumor biopsy is required; an on-treatment biopsy is required after 30 days or 2 cycles of treatment but before start of cycle 3. The end of visit biopsy is only required 
if this was obtained for acute organ rejection or GVHD in which case the involved organ (kidney, skin, GI tract) should be biopsied and not the tumor 
N research peripheral blood samples required (see Section 9.1 for details about collection) 
O Adverse event evaluations should be recorded using CTCAE version 5.0 
P only in Cohort 1, patients require both acute GVHD score (Section 7.6) and chronic NIH GVHD scoring (Section 7.7) if there is clinical concern for the development of GVHD 
Q baseline screening evaluations (except for informed consent and imaging, see Footnote L) are to be conducted within 2 weeks [14 days, ± 5 days] of the start of protocol therapy 
(either cemiplimab in Cohort 1, or the lead-in phase for Cohort 2) 
R follow-up beyond the study should include routine check-ins every 3-4 months up to 12 months or 1 year from EOT visit, which can overlap with routine clinic visits or include 
telephone encounters 
S research urine samples collected as at least 100 mL aliquots in a standard sample cup will be obtained at screening and each cycle visit; if local labs are collected then day 8, 15 
urine samples for research can be skipped 
 
 
 
 
 
 
38 


 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 8 weeks 
through cycle 10 at which point restaging scans can occur every 12 weeks. In addition to a 
baseline scan, confirmatory scans should also be obtained (not less than 4) weeks following 
initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[43] and by WHO response criteria [44]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. Changes in the sum of the products of the two longest 
diameters in perpendicular directions (bidimensional measurements) are used in the WHO 
criteria. 
 
11.1.1 Definitions 
Evaluable for Target Disease response. Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response. These 
participants will have their response classified according to the definitions stated below. 
(Note: Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease. The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
 
11.1.2 Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with 
CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area may be considered 
measurable. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
 
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Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short 
axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/lung parenchymal inflammation, 
inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic 
lesions are all considered non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- 
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
 
Target lesions (per RECIST v1.1). All measurable lesions up to a maximum of 2 lesions 
per organ and 5 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of 
all involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. A sum of the diameters (longest 
for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. For the purpose of this study, when using WHO criteria, up to 5 
lesions are measured, or are deemed target lesions. 
 
Non-target lesions (per RECIST v1.1). All other lesions (or sites of disease) including 
any measurable lesions over and above the 5 target lesions should be identified as non- 
target lesions and should also be recorded at baseline. Measurements of these lesions are 
not required, but the presence, absence, or in rare cases unequivocal progression of each 
should be noted throughout follow-up. 
 
11.1.3 Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
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each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm in diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used, and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all (target) lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to < 10 
mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters per RECIST v1.1. At least a 


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50% reduction in the sum of the products of the two longest diameters among all 
lesions per WHO criteria. 
Progressive Disease (PD): Per RECIST v1.1, at least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. Per WHO criteria, at least a 25% increase in the sum of the product of the two 
longest diameters among all lesions, or at least 25% increase in any 1 lesion. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study per both RECIST v1.1 and WHO criteria. 
11.1.4.2 
Evaluation of Non-Target Lesions for RECIST v1.1 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm 
short axis). 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new. If a new 
lesion is equivocal (because of small size etc.), follow-up evaluation will clarify if it 
truly represents new disease and if PD is confirmed, progression should be declared 
using the date of the initial scan on which the lesion was discovered. 
 
11.1.4.4 
Second Primary Cutaneous and Other Malignancies 


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Given this study involves high-risk and immunosuppressed transplant survivors, the 
finding of a new, spatially or regionally distinct (not in-transit) non-melanomatous 
skin cancer (squamous cell carcinoma) thought to be a second primary is not 
considered a new lesion for the definition of PD. In addition, the development of a 
second primary malignancy with squamous histology (in the lungs, head and neck) is 
also not considered a new lesion for the definition of PD. 
11.1.4.5 
Treatment Beyond Disease Progression 
 
The decision to treat any study participant beyond progression of disease is at the 
discretion of the treating investigator and can be discussed with the Overall PI. 
Patients who are assigned a best response of PD at any time point can continue on- 
study treatment if the patient is receiving some reasonable clinical benefit and is 
tolerating the study drug. 
 
Patients treated beyond disease progression should be re-consented at the time of 
initial imaging showing possible progression to ensure they are aware of alternative 
therapies and investigational options that may be available in lieu of continued study 
treatment. 
 
In this scenario, it is recommended that repeat restaging imaging be performed 4-6 
weeks after the documentation of PD to re-evaluate for ongoing clinical benefit. 
 
 
11.1.4.6 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) per RECIST v1.1 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
> 4 wks Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
> 4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not evaluated 
No 
SD 
Documented at least once > 4 wks 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See Section 11.4.1.3 for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 


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For Participants with Non-Measurable Disease (i.e., Non-Target Disease) per RECIST v1.1 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
 
11.1.5 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
 
11.1.6 Progression-Free Survival 
Overall Survival: Overall Survival (OS) is defined as the time from registration to death 
due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
registration to the earlier of progression or death due to any cause. Participants alive 
without disease progression are censored at date of last disease evaluation. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Participants with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” 
Every effort should be made to document the objective progression even after discontinuation of 
treatment. 


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Duration of Response: Time from documentation of PR or CR at first reporting (later 
confirmed with 4-week imaging) to time of progression or censored at date of last disease 
evaluation. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
12.1.2 Responsibility for Data Submission 
Study team is responsible for entering data in the eDC system (InForm), within the 
timeframe, in accordance with DF/HCC SOPs. 
 
Tumor genomic and molecular profiling results that are available or become available 
during the study will be recorded during study participation. 
 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
 
13. STATISTICAL CONSIDERATIONS 
 
This study is not designed for statistical hypothesis testing. 


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Original biostatistical design: 
The 3+3 design is adapted to determine the safety and toxicity of immunotherapy in Cohort 1 
and Cohort 2. To that end, while accrual is expected to be slow, we will approve two patients to 
enroll into to each cohort at a time to monitor toxicity appropriately. For each cohort, the 
maximum sample size is 12. The actual sample size is dependent upon observed GVHD rate or 
acute organ rejection rate. The assessments will be done when up to 12 patients have been 
enrolled and observed in each cohort. For Cohort 1, a GVHD rate exceeding 33% is considered 
unacceptable. The following table shows the stop rule: 
 
Number of patients treated in Cohort 1 3 6 12 
Stop recruitment if # of GVHD ≥ 
2 3 6 
 
For Cohort 2, a renal transplant rejection rate exceeding 60% is considered unacceptable. This 
cutoff was selected given that recently published data including 23 renal transplant recipients 
who received various checkpoint inhibitors experienced a 50% rate of acute kidney rejection [19] 
on variable immunosuppressive regimens. Since enrolled subjects in the current study have 
incurable, metastatic, and life-threatening cutaneous SCC, the investigators feel that an acute 
renal graft rejection rate above 60% would mitigate the exposure risk to PD-1 blockade in the 
present study. Therefore, the following table shows the stop rule: 
 
Number of patients treated in Cohort 2 3 6 12 
Stop recruitment if # of rejection ≥ 
2 4 6 
 
Modified biostatistical design: Due to slower than expected accrual in Cohort 1 and the 
observation of safety and efficacy in Cohort 2, the Sponsor-Investigator and study team 
discussed closure of Cohort 1 with a focus on Cohort 2 in November 2021. No patients enrolled 
to Cohort 1. With those updates, the final sample size was set at a maximum of 12 patients 
overall (in Cohort 2 only). 
 
13.1 
Study Design/Endpoints 
 
Primary Endpoints: To determine the safety and toxicity of immunotherapy in advanced 
cutaneous squamous cell carcinoma (cSCC) patients having undergone prior hematopoietic stem 
cell or renal transplant. 
 
Secondary Endpoints: To evaluate the anti-tumor activity and survival benefit in advanced 
cSCC patients receiving immunotherapy despite a history of transplant: 
• To estimate progression-free survival (PFS) and overall survival (OS) 
• To estimate duration of therapeutic response 
• To estimate the propensity for secondary infection on treatment 
Follow-up visits will occur every 3-4 months up to 1 year. Accrual is expected to be slower than 
other therapeutic protocols given the rarity of the condition, but we expect 1 patient to enroll 


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every 3 months among each cohort (1 renal transplant patient, and 1 stem cell transplant patient) 
which would result in an estimated 18 months or 1.5 years to accrue the study. 
13.2 
Stratification Factors 
 
There are no planned stratification factors. 
 
13.3 
Analysis of Primary Endpoints 
 
Patient safety will be assured by monitoring the proportions of patients who have 
observed GVHD in Cohort 1 or renal transplant rejection in Cohort 2 when 3 to 12 
patients have been enrolled into each cohort. 
Participants will be evaluable for toxicity from the time of their first treatment. The 
toxicity will be presented in frequency tables (overall and by cohort). In tables 
showing the overall incidence of adverse events, patients who experienced the same 
event on more than one occasion will be counted only once in the calculation of the 
event frequency. The worst grade of an event will be reported for any patient. 
13.4 
Analysis of Secondary Endpoints 
 
Time-to-event endpoints will be summarized using the method of Kaplan-Meier. 
Point estimates for each endpoint will be presented with 90% confidence intervals 
derived using log(-log(survival)) methodology. The other secondary endpoints 
including anti-tumor activity will be summarized descriptively. 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in Section 13 on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 


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Hodgkin lymphoma. Blood, 2017. 129(18): p. 2471-78. 
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François S, Stamatoullas-Bastard A, Rohrlich PS, Labussière Wallet H, Castagna L, 
Santoro A, Bachanova V, Bresler SC, Srivastava A, Kim H, Pesek E, Chammas M, 
Reynolds C, Ho VT, Antin JH, Ritz J, Soiffer RJ, Armand P, Safety and efficacy of 
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Godfrey J, B.M., Syed S, Hyjek E, Kline J, PD-1 blockade induces remissions in 
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Tio M, R.R., Ezeoke OM, McQuade JL, Zimmer L, Khoo C, Park JJ, Spain L, Turajlic S, 
Ardolino L, Yip D, Goldinger SM, Cohen JV, Millward M, Atkinson V, Kane AY, 
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L, Cambon N, Boger R, Kovarik JM; Everolimus Study Group, Single-dose 
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Eisen H, Tai SS, Kushwaha S, Randomized controlled trial of sirolimus conversion in 
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30. 
Strueber M, W.G., Fuge J, Simon AR, Zhang R, Welte T, Haverich A, Gottlieb J, 
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Hirayama Y, G.M., Yamano S, Tachibana H, Okuno T, Tamada S, Nakatani T, 
Wanibuchi H, Anti-PD-L1 treatment enhances antitumor effect of everolimus in a mouse 
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A, R., Tumor immunotherapy directed at PD-1. N Engl J Med, 2012. 366(26): p. 2517-9. 
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checkpoint inhibition in solid organ transplants: 2 sides of a coin - case report. BMC 
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35. 
Holdaas H, D.S.P., Zuckermann A, Everolimus and Malignancy after Solid Organ 
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Lipson EJ, B.S., Moore J Jr, Jang S, Patel MJ, Zachary AA, Pardoll DM, Taube JM, 
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Miller DM, F.-J.B., Stone JR, Drews RE, Complete pathologic response of metastatic 
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Eisenhauer EA, T.P., Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
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Verweij J, New response evaluation criteria in solid tumours: revised RECIST guideline 
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1981. 47: p. 207-14. 


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APPENDIX A 
CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION (CKD- 
EPI) EQUATION 
 


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


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APPENDIX C 
GUIDANCE ON CONTRACEPTION 
 
Highly Effective Methods of Contraception: 
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to use one of the 
highly effective methods of contraception listed below. Male subjects must inform their female partners 
who are WOCBP of the contraceptive requirements of the protocol and are expected to adhere to using 
contraception with their partner. 
 
At a minimum, subjects must agree to use one highly effective method of contraception as listed below: 
 
For WOCBP highly effective methods of birth control include the following: 
• Progestogen only hormonal contraception associated with inhibition of ovulation 
• Hormonal methods of contraception including oral contraceptive pills 
(combination of estrogen and progesterone), vaginal ring, injectables, or implants 
• Intrauterine devices (IUDs) (hormonal or non-hormonal) 
• Intrauterine Hormone-releasing System (IUS) 
• Bilateral tubal ligation 
• Vasectomy 
• Complete abstinence (complete avoidance of heterosexual intercourse) 
 
For male subjects with partners that are WOCBP: 
• Condom 
 
All male subjects who have partners who are WOCBP must use condoms as their second method of 
contraception. 
 
Women of childbearing potential (WOCBP) receiving cemiplimab will be instructed to adhere to 
contraception for a period of 7 months after the last dose of investigational product. Men receiving 
nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a 
period of 7 months after the last dose of investigational product. These durations have been calculated 
using the upper limit of the half-life for cemiplimab (25 days) and are based on the protocol requirement 
that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with 
WOCBP use contraception for 5 half-lives plus 90 days after the last dose of cemiplimab. 


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APPENDIX D 
IMMUNE-MEDIATED TOXICITY MANAGEMENT ALGORITHMS 
 
• 
These general guidelines constitute guidance to the Investigator. The guidance applies to all 
immuno-oncology (I-O) agents and regimens. 
• 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
• 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low- 
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
• 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
• 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used. 


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APPENDIX E 
NIH CONENSUS FORM FOR SCORING CHRONIC GVHD 
 


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SAP_001.pdf: 
1 
 
NCT04339062 
A Phase I Study of the Safety and Efficacy of Cemiplimab (PD-1 blockade) in 
Selected Organ Transplant Recipients with Advanced Cutaneous Squamous Cell 
Carcinoma (CONTRAC) 
DFCI Protocol #: 19-817 
 
Statistical Analysis Plan 
March 20, 2022 
 
 


2 
 
Design: This protocol was designed as an open-label, two cohort, phase I study of immune checkpoint 
blockade with cemiplimab in patients with advanced cutaneous squamous cell carcinoma (cSCC) who 
have previously undergone an allogeneic hematopoietic stem cell transplant (HSCT) or renal allograft 
transplantation. Patients were divided into two cohorts based on their history of prior HSCT for a 
lymphoproliferative disorder or hematologic malignancy (Cohort 1), or a history of prior renal 
transplantation (Cohort 2). In the rare event that a patient had a history of both prior HSCT and prior 
renal transplantation, the patient would be included in Cohort 2. Following biopsy, screening, and 
enrollment, participants in Cohort 1 would receive cemiplimab at standard dosing (350 mg IV every 21 
days) until disease progression or unacceptable toxicity (including graft-versus- host disease [GVHD]), 
whichever occurred first. Cohort 2 mandated that the patient follow a standard immunosuppressive 
regimen that included: everolimus or sirolimus with monitored trough levels to ensure therapeutic 
levels, in addition to prednisone pulse dosing corresponding to each dose of cemiplimab (prednisone 40 
mg daily 1 day prior to cemiplimab, followed by 40 mg daily on the day of and up to 2 additional days 
after dosing, then 20 mg for 3 days, followed by 10 mg daily thereafter until the day prior to redosing of 
cemiplimab when the prednisone cycle repeated). Prophylactic antibiotics were permitted at the 
discretion of the treating physician while the patient was on immunosuppression and for the duration of 
the study. Treatment continued in Cohort 2 with cemiplimab at standard dosing (350 mg IV every 21 
days) until unacceptable toxicity (acute allograft rejection) or disease progression. Our aim was to 
evaluate the safety and efficacy of cemiplimab in this high-risk but in-need population, and utilize a 
standard, augmented immunosuppression regimen to minimize the risk of immune-related toxicity, 
specifically organ transplant rejection. 
 
Original Design: The 3+3 design was adapted to determine the safety and toxicity of immunotherapy in 
Cohort 1 and Cohort 2. To that end, while accrual was expected to be slow, two patients were to enroll 
into each cohort at a time to monitor toxicity appropriately. For each cohort, the maximum sample size 
was 12. The actual sample size was dependent upon the observed GVHD rate or acute organ rejection 
rate. Endpoint assessments would be done when up to 12 patients had been enrolled and observed in 
each cohort. For Cohort 1, a GVHD rate exceeding 33% was considered unacceptable. The following table 
shows the stopping rule: 
 
Number of patients treated in Cohort 1 
3 6 
12 
Stop recruitment if # of GVHD ≥ 
2 3 
6 
 
For Cohort 2, a renal transplant rejection rate exceeding 60% was considered unacceptable. This cutoff 
was selected given that previously published data, including 23 renal transplant recipients who received 
various checkpoint inhibitors, experienced a 50% rate of acute kidney rejection on variable 
immunosuppressive regimens. Since enrolled subjects in the current study had incurable, metastatic, and 
life-threatening cutaneous SCC, the investigators felt that an acute renal graft rejection rate above 60% 
would mitigate the exposure risk to PD-1 blockade in the present study. Therefore, the following table 
shows the stopping rule: 
 
Number of patients treated in Cohort 2 
3 
6 12 
Stop recruitment if # of rejections ≥ 
2 
4 6 
 
Modified biostatistical design: Due to slower than expected accrual in Cohort 1 and the observation of 
safety and efficacy in Cohort 2, the Sponsor-Investigator and study team discussed closure of Cohort 1 
with a focus on Cohort 2 in November 2021. No patients enrolled in Cohort 1. With those updates, the 


3 
 
final sample size was set at a maximum of 12 patients overall (in Cohort 2 only).  The analysis plan is 
presented for Cohort 2 only. 
 
Endpoints 
 
Primary Endpoint: The primary end point was safety and toxicity, specifically the rate of kidney allograft 
rejection or loss (GVHD).  Adverse events to assess the safety and side-effect profile of cemiplimab were 
recorded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
 
Secondary Endpoints: 
a.  
 Objective antitumor response:  Best overall response (complete response (CR) or partial response 
(PR)) per RECIST 1.1.   
b.   
Progression-free survival (PFS): Time from date of enrollment until objective disease progression 
(per RECIST) or death, whichever occurred first. For patients without progression, follow-up was censored 
at the date of last adequate restaging.   
c.   
Overall survival (OS): Time from enrollment to death from any cause. For patients lost to follow-
up or who had no documentation of death at the time of final analysis, follow-up was censored at the 
date of last assessment of vital status. 
d. 
Duration of response:  Estimated only in patients with objective response.  The time between the 
date when response was originally suspected until documented disease progression.  The follow-up of 
patients who did not progress was censored at the date of last adequate restaging. 
 
 
 


4 
 
Variables and Derived Data 
 
1.  Patient Enrollment and Demographics 
 
CRF: q_demo 
 
Variable Name 
Values 
Casenum  
Patient ID 
Dt_regdt 
Study registration date 
Dt_birthdt 
Date of birth 
D_sex 
Sex 
D_race 
Race 
D_ethnicity 
Ethnicity 
 
Code for age (years): 
 
age = floor((dt_regdt - dt_birthdt)/365.25); 
 
 
2. Disease Characteristics 
 
CRF: q_studyentry 
Variable Name 
Values 
Dt_dtdiag 
Date of original diagnosis 
Dt_dtmetadiag 
Date metastatic diagnosis 
D_primarysite 
Primary site of initial diagnosis 
D_side 
 
Side of disease 
D_site 
Site of recurrent disease 
D_stage 
Stage at initial diagnosis 
D_diseasestagerec 
Stage at local/regional recurrence 
D_smokingstatus 
Smoking status 
D_alcohohistyn 
Alcohol history 
 
Years between initial diagnosis and enrollment: 
yrs_post_pdiag = (dt_regdt - DT_DTDIAG)/365.25; 
 
Weeks to local/regional recurrence: 
wks_met_recur = (DT_DTMETADIAG - dt_dtdiag)/7; 
 
3. Prior Therapies 
CRF: q_priortx 
Variable Name 
Values 
D_chemoyn 
Prior chemotherapy 
D_radyn 
Prior radiation therapy 
D_targyn 
Prior targeted therapy 
D_priorsurgyn 
Prior surgery 
 
 


5 
 
4.  Response to Therapy 
 
CRF: q_response 
Variable Name 
Values 
D_overall 
Best response to therapy 
DT_DTOVERALLRESP 
Date best overall response 
 
5. Cycles Therapy Attempted 
 
CRF: q_cemiplimimab 
 
if (date of administration) not missing. 
proc freq; table casenum; ods output onewayfreqs=owf; run; 
proc means data = owf n mean std min median max; run; 
 
6.  On-study Toxicities 
 
CRF: q_ae 
Variable Name 
Values 
toxcode 
CTCAE toxicity code 
C_toxgrd 
Toxicity grade 
C_attrib 
Relatedness to therapy (if 2, 3, 4 then deemed 
at least possibly related) 
toxdesc 
Text for toxicity 
toxcat 
Medra System Organ Class 
dltxx 
Was event a DLT? 
cmnts 
Description text for toxicities coded as “other” 
 
Toxicities presented according to worst grade occurring per patient: 
Proc sort data=tox; by subject toxcode descending c_toxgrd; 
 
data tox_unique; 
set tox; by casenum toxcode; 
if first.toxcode; 
if index(toxdesc,"Other") gt 0 then toxdesc = propcase(cmnts); 
run; 
 
proc tabulate data=tox_unique format=6.1; 
class toxcode toxdesc toxcat c_toxgrd/style={font_weight=bold}; 
table toxcat="System-Organ Class"*toxdesc = "Description",(all="Number patients" 
c_toxgrd="Grade")*N/misstext="-"; 
run; 
 
To select toxicities that are at least possibly related to therapy: 
Subset to those events where c_attrib is 2, 3, or 4. 
 
 


6 
 
 
7.  Deaths and Overall Survival 
 
CRF: q_followup 
Variable Name 
Values 
Dt_dtstatus 
Month/day/year death or last follow-up 
C_ptstatus 
Patient status (death = 2) 
 
 
Code for Overall survival: 
data os; 
*Need date of enrollment: dt_regdt; 
if c_ptstatus = 2 then os_cns = 1; 
else os_cns = 0; 
os_mos = (dt_dtstatus - dt_regdt)/30.4375; 
run; 
 
8.  Time to Progression 
 
CRF: q_response 
Variable Name 
Values 
C_overall 
Value = 5 for patients with PD 
dt_dtoverallresp 
Date of disease progression 
 
Code for PFS  
proc sort; by casenum DT_DTOVERALLRESP; 
run; 
 
data firstpd; 
set pd; by casenum; 
if first.casenum; 
run; 
 
data pfs; 
merge os (in=o) firstpd(in=p); by casenum; if o; 
if p or os_cns = 1 then pfs_cns = 1; else pfs_cns = 0; 
if pfs_cns = 1 then pfs_mos = (min(last_date,dt_dtoverallresp) - 
dt_regdt)/30.4375; 
else pfs_mos = os_mos; 
 
 
 
 
 


7 
 
Statistical Analyses 
 
Primary Endpoints 
Safety and toxicity 
a.  Rates of GVHD 
Proportion of patients who developed GVHD as a result of therapy.   
b.  Rates of Grade 3-5 adverse events 
Proportion of patients with at least one grade 3, 4, or 5 adverse event. 
  
Both rates will be accompanied by 90% exact binomial confidence intervals. 
 
Secondary Endpoints 
a.  Overall Survival and Progression-Free Survival 
The distributions of progression-free and overall survival will be summarized using the method of 
Kaplan-Meier. Median times for each therapy arm will be accompanied by 90% confidence 
intervals based on log(-log(endpoint)) methodology.  
       b.      Response Rate 
The proportion of patients who had best RECIST response of CR or PR.  The denominator is the number 
of patients with at least one scan to assess RECIST.  One patient died before such a scan, resulting in a 
denominator of 11 patients.  Response rate will be summarized with a 90% exact binomial confidence 
interval.