Conditions: Metastatic Pancreatic Cancer
Keywords: Plerixafor Cemiplimab Immunotherapy PD-L1 (receptor blocking antibody) Anti-PD-L1 CXCR4 (chemokine receptor) Antibodies Metastatic pancreatic cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and clinical activity of plerixafor in combination with cemiplimab in patients with metastatic pancreatic cancer.

Detailed description:

Arms:
arm 1: All participants will receive Cemiplimab and Plerixafor.

Interventions: intervention 1: Cemiplimab intervention 2: Plerixafor
Intervention descriptions: intervention 1: Cemiplimab (350 mg) will be administered IV on day 1 of each cycle (21 day cycle) for up to 2 years. intervention 2: Plerixafor (80mcg/kg/hr) will be administered as a continuous IV infusion of the first 7 days of each cycle (21 day cycle) for up to 2 years.

Protocol document:
Prot_SAP_000.pdf: 
Cover Page for Protocol – J19113 
NCT Number: 
NCT04177810 
Official title of study 
A Phase 2 Study of Plerixafor and 
Cemiplimab in Metastatic Pancreatic 
Cancer 
Document Date: 
May 13, 2022 


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TITLE:  A Phase 2 Study of Plerixafor and Cemiplimab in Metastatic Pancreatic Cancer 
 
Johns Hopkins Protocol #:   J19113, IRB00225153 
 
Sanofi Protocol #:    
SGZ-2018-12345 
 
Principle Investigator (Protocol Chair): 
 
 
Dung Le, M.D.  
 
Sidney Kimmel Comprehensive Cancer Center, 
 
 
 
 
Johns Hopkins University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sanofi/Genzyme Supplied Agent: Plerixafor (AMD3100, Mozobil) 
Regeneron Supplied Agent:  
Cemiplimab (REGN-2810, Libtayo) 
 
 
IND:  
 
 
IND Exempt 
 
Date of Issue:  
 
Original/Version 1/August 9, 2019 
Original/Version 1.1/November 7, 2019 
Amendment 1/Version 2.0/July 1, 2020 
Amendment 2/Version 3.0/August 11, 2020 
Amendment 3/Version 4.0/January 28, 2021 
Amendment 4/Version 5.0/August 9, 2021 
Amendment 5/Version 6.0/January 12, 2022 
Amendment 6/Version 7.0/May 13, 2022 
 


 
2
Table of Contents 
1. 
Objectives .......................................................................................................................... 4 
1.1. 
Primary Objective ............................................................................................................... 4 
1.2. 
Secondary Objectives ......................................................................................................... 4 
1.3. 
Exploratory Objectives ....................................................................................................... 4 
1.4. 
Study Design ....................................................................................................................... 5 
2. 
Background ....................................................................................................................... 6 
2.1. 
Study Disease ...................................................................................................................... 6 
2.2. 
Dual Blockade of PD-1 and CXCR4 .................................................................................. 7 
2.3. 
Dose Selection .................................................................................................................... 8 
2.4. 
Rationale ............................................................................................................................. 8 
3. 
Patient Selection .............................................................................................................. 11 
3.1. 
Eligibility Criteria ............................................................................................................. 11 
3.2. 
Exclusion Criteria ............................................................................................................. 13 
3.3. 
Inclusion of Women and Minorities ................................................................................. 15 
4. 
Treatment Plan ............................................................................................................... 15 
4.1. 
Agent Administration ....................................................................................................... 15 
4.2. 
General Concomitant Medication and Supportive Care Guidelines ................................. 16 
4.3. 
Prohibited and/or Restricted Treatments .......................................................................... 18 
4.4. 
Other Restrictions and Precautions ................................................................................... 19 
4.5. 
Permitted Therapy ............................................................................................................. 19 
4.6. 
Definition of an Overdose for this Protocol ...................................................................... 20 
4.7. 
Unacceptable Toxicity ...................................................................................................... 20 
4.8. 
WOCBP, Contraception, Use in Pregnancy, Use in Nursing ........................................... 20 
4.9. 
Duration of Therapy .......................................................................................................... 24 
4.10. 
Criteria for Removal from Treatment ............................................................................... 24 
4.11. 
End of Treatment (EOT) ................................................................................................... 27 
4.12. 
Duration of Follow Up ...................................................................................................... 27 
5. 
Dosing Delays/Dose Modifications ................................................................................. 28 
5.1. 
Dose Modifications ........................................................................................................... 28 
5.2. 
Dose Delays ...................................................................................................................... 28 
6. 
Adverse Events: List and Reporting Requirements .................................................... 29 
6.1. 
Definitions ........................................................................................................................ 29 
6.2. 
Relationship ...................................................................................................................... 31 
6.3. 
Expectedness ..................................................................................................................... 32 
6.4. 
Handling of Expedited Safety Reports ............................................................................. 32 
6.5. 
Reporting .......................................................................................................................... 33 
7. 
Pharmaceutical Information .......................................................................................... 35 
7.1. 
Cemiplimab ....................................................................................................................... 35 
7.2. 
Plerixafor .......................................................................................................................... 37 
8. 
Correlative/Special Studies ............................................................................................ 40 
8.1. 
Tumor Tissue Studies ....................................................................................................... 40 
8.2. 
Whole Blood ..................................................................................................................... 41 
8.3. 
Peripheral Blood Mononuclear Cells (PBMCs)................................................................ 41 
8.4. 
Serum and Plasma Marker Studies ................................................................................... 41 
8.5. 
Serum and Salivary Cortisol ............................................................................................. 41 


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8.6. 
CT Scans for Body Composition ...................................................................................... 42 
8.7. 
Diagnostic Tissue Samples ............................................................................................... 42 
8.8. 
Genomic Analysis ............................................................................................................. 42 
9. 
Study Calendar ............................................................................................................... 43 
10. 
Study Endpoints .............................................................................................................. 47 
10.1. 
Primary Endpoint .............................................................................................................. 47 
10.2. 
Secondary Endpoints ........................................................................................................ 47 
10.3. 
Exploratory Endpoints ...................................................................................................... 47 
11. 
Data Reporting/ Regulatory Requirements .................................................................. 48 
11.1. 
Data Collection and Processing ........................................................................................ 48 
11.2. 
Safety Meetings ................................................................................................................ 49 
11.3. 
Monitoring ........................................................................................................................ 49 
11.4. 
Study Documentation ....................................................................................................... 49 
12. 
Statistical Considerations ............................................................................................... 51 
12.1. 
Study Design/Endpoints ................................................................................................... 51 
12.2. 
Safety Analysis ................................................................................................................. 52 
13. 
References ........................................................................................................................ 54 
APPENDIX A: Performance Status Criteria ......................................................................................... 55 
APPENDIX B: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .......................................................................... 56 
APPENDIX C: Description of the iRECIST Process For Assessment of Disease Progression .......... 59 
APPENDIX D: SAE Reporting Form ..................................................................................................... 64 
APPENDIX E: AESI Reporting Form .................................................................................................... 67 
 
 
 
 
 


 
4
1. 
OBJECTIVES 
 
1.1. 
Primary Objective 
 
To estimate the objective response rate (ORR) using immune RECIST (iRECIST) in patients with 
metastatic pancreatic cancer treated with plerixafor and cemiplimab. 
 
1.2. 
Secondary Objectives 
 
1.2.1. To estimate ORR using RECIST v.1.1. 
 
1.2.2. To assess safety and characterize toxicities of plerixafor in combination with 
cemiplimab. 
 
1.3. 
Exploratory Objectives 
 
1.3.1. To assess progression free survival (PFS), time to progression (TTP), disease control 
rate (DCR), best overall response (BOR), duration of response (DOR), duration of 
clinical benefit (DCB), and time to objective response (TTOR) using, iRECIST and 
RECIST v.1.1. 
 
1.3.2. To assess the overall survival (OS).  
 
1.3.3. To measure pharmacokinetic and pharmacodynamic parameters in pancreatic 
cancer patients treated with plerixafor and cemiplimab including but not limited to 
increase numbers of CD34+ cells in the blood.  
 
1.3.4. To collect pre- and on-treatment biopsies to explore the association of features of 
the tumor microenvironment in response to therapy, including but not limited to 
assessment of: 
 T cell subset markers (CD4, CD8, FoxP3, Granzyme A/B, CD69), immune 
regulation (PD-L1, PD-L2, CTLA4, LAG-3, IDO1, TIM-3), and immune cell 
population markers (NK, DC, B cell, MDSC, etc.).  Techniques used for 
analyses may include but are not limited to immunohistochemistry (IHC) and 
mass cytometry.   
 Transcriptomics using single-cell RNASeq analysis.  Immune cell numbers and 
activation state will be characterized. 
 CXCR4 and CXCL12 IHC 
 
1.3.5.  To evaluate molecular determinants of response using next generation sequencing 
and other sequencing techniques. 
 
1.3.6. To collect peripheral blood mononuclear cells (PBMC) and serum to identify 
potential therapeutic targets, biomarkers and predictors of response (OS, PFS and 
best overall response).  


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 Measure pre- and post-treatment changes in PBMCs including effector, helper, 
and regulatory T cells, NK cells, monocytes, and macrophages through cell 
phenotyping analysis and gene expression profiling.  
 
 Proteomic approaches will be used on pre- and post-treatment sera to identify 
targets and biomarkers of response or toxicity. 
 
1.3.7. To evaluate clonal T cell populations in the tumor and in the periphery through T 
cell receptor sequencing, and to functionally assess mutation associated 
neoantigen-specific T cells. 
 
1.3.8.  To measure serum and salivary cortisol levels and correlate with response and 
immune cell infiltration. 
 
1.3.9. To use CT imaging for body composition analyses and correlate with outcomes. 
 
1.3.10. To measure changes in cfDNA content and quantity in response to therapy. 
 
1.4. 
Study Design 
 
This is a single center, phase II trial in patients with previously-treated metastatic pancreatic 
cancer.  There will be a safety run-in (n=6). Plerixafor will be administered at 80 mcg/kg/hr x 24 
hours per day x 7 days each cycle. The cycle will be repeated every three weeks. Cemiplimab will 
be administered on day 1 of each cycle at a dose of 350mg by intravenous infusion.  Tumor 
biopsies will be obtained at baseline and on either Cycle 1 Day 8 or Cycle 2 Day 1 for alternating 
patients.  An optional biopsy may be obtained at the time of disease progression. 
 
The primary endpoint is objective response rate (irORR: CR + PR) per iRECIST.  The treatment 
regimen would be considered of insufficient activity for further study in this population if the 
irORR is 7.7% or less, and the minimum required level of efficacy that would warrant further study 
is an irORR of 20%.  The sample size is calculated to detect an improved irORR from 7.7%[1] to 
20%. A modified Simon’s two-stage design is planned. A total of 21 patients will be entered in the 
first stage. If <=1 subject responds, the treatment will be terminated and we will conclude the 
regimen is ineffective. If >=2 subjects respond, then additional 18 patients will be enrolled.  If a 
total of 5 or fewer subjects respond in stage one and two combined, we consider the regimen 
ineffective. If a total of 6 or more respond, we conclude the regimen is promising and warrant 
further study. The maximum sample size will be 39. 
 
The study will consist of a pre-screening period, a screening period (within 28 days of the first 
dose), a treatment period, and a follow-up period.  Subjects will receive treatment on 21 day cycles, 
and will come to clinic for dosing and/or assessments on Day 1 of each cycle and additional days 
for safety and immune monitoring follow up as per the study schedule in Section 9. No dose 
escalations or reductions of plerixafor or cemiplimab are allowed. Complete information on study 
drug administration, schedule, and dosing can be found in Section 4.1. 
 


 
6
The study will include a safety run-in for the first six patients. If more than 1 of the first 6 patients 
experiences an unacceptable toxicity within the first cycle, then enrollment will be halted and the 
overall risk-benefit ratio of the study will be reconsidered. At any time thereafter, if more than 
33% of patients are observed to experience unacceptable toxicity within the first cycle, enrollment 
will be halted and the safety of the combination will be re-evaluated. Complete unacceptable 
toxicity criteria can be found in Section 4.7. 
 
Treatment may continue up to a maximum of 2 years, or until discontinuation due to toxicity, lack 
of clinical benefit as determined by the investigator, subject withdrawal, or termination of the 
study. Subjects may continue on treatment with radiographic disease progression if subject is 
clinically stable and investigator believes the treatment is providing benefit. Criteria for removal 
from treatment are found in Section 4.10.  
 
Tumor biopsies, PBMC, serum and plasma collection, and computed tomography (CT) scans or 
magnetic resonance imaging (MRI), if CT is contraindicated, will be obtained at baseline and 
during treatment for clinical assessments and correlative analyses. Tumor assessments will be 
made using RECIST 1.1/iRECIST. 
 
Subjects will return to the study site 30 (+/- 7) days after the final administration of study treatment 
for an end of treatment (EOT) evaluation. Subjects will be considered in the treatment period until 
30 days after the last dose of study drug. After completion of treatment and EOT assessments, all 
subjects will continue to be followed per Section 4.12. 
 
Information on progression-free survival and overall survival may continue to be gathered for 
supplementary analyses after the completion of the primary analysis.  
 
2. 
BACKGROUND 
 
2.1. 
Study Disease 
 
Despite decades of basic and clinical research, effective therapy for the treatment of patients with 
pancreatic ductal adenocarcinoma (PAC) remains one of the greatest unmet clinical needs in 
oncology today. Currently, PAC accounts for approximately 7% of all cancer-related mortality 
and has the lowest 5-year survival rate among all cancer types in the United States. PAC is 
currently the 4th leading cause of death from cancer in the U.S. with estimates in 2016 for 53,070 
people diagnosed and about 41,780 dying from the disease [2].  Worldwide it will claim more than 
300,000 lives this year [3].  It is projected that by 2030, pancreatic cancer will become the second 
leading cause of cancer-related death in the US [4].  
 
Most patients are initially diagnosed with advanced disease that is inoperable with median survival 
of less than 1 year. Patients with advanced disease are usually treated with chemotherapy, with the 
intent of prolonging survival and palliating symptoms (pain, weight loss and decrease in 
performance status). From 1997, gemcitabine was the standard chemotherapy for advanced 
pancreatic cancer after demonstrating a significant improvement in survival compared to 5-
fluorouracil (5-FU) [5]. Median survival was 5.65 months for gemcitabine-treated patients and 


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4.41 months for 5-FU treated patients, while overall tumor response rates were 5.4% and 0%, 
respectively. 
 
Until recently, only erlotinib, an oral epidermal growth factor (EGF) inhibitor, was shown in a 
Phase 3 study to modestly improve median OS in combination with gemcitabine over gemcitabine 
alone (6.24 months for the doublet versus 5.91 months for gemcitabine alone) without a significant 
difference in ORR between the treatments [6]. In 2011, a Phase 2/3 trial conducted by a French 
consortium study group demonstrated FOLFIRINOX, a combined regimen of oxaliplatin, 
irinotecan, fluorouracil, and leucovorin significantly increased survival in patients with pancreatic 
cancer over gemcitabine alone. Median OS was 11.1 months versus 6.8 months for each treatment, 
respectively (hazard ratio [HR] for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; p < 
0.001). The ORR was also increased to 31.6% from 9.4% (p < 0.001). Adverse events were 
increased in the FOLFIRINOX group and 5.4% of patients in this group experienced febrile 
neutropenia [7]. Although FOLFIRINOX represents an efficacious regimen in pancreatic cancer, 
there are still concerns about its potential toxicity and it is being reserved for the most fit patients. 
 
In the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, nab-paclitaxel 
combined with gemcitabine demonstrated a statistically significant and clinically meaningful 
median OS of 8.5 versus 6.7 months (HR 0.72, p < 0.0001 including a 59% increase in one-year 
survival (35% versus 22%, p=0.0002) and demonstrated double the rate of survival at two years 
(9% versus 4%, p=0.02) as compared to gemcitabine alone in previously untreated patients with 
metastatic pancreatic cancer. nab-/gemcitabine also demonstrated a statistically significant 
improvement in key secondary endpoints compared to gemcitabine alone, including a 31% 
reduction in the risk of progression or death with a median PFS of 5.5 versus 3.7 months (HR 0.69, 
p < 0.0001) and an ORR of 23% compared to 7% (response rate ratio of 3.19, p < 0.0001)[8]. The 
MPACT study and regimen formed the basis for full FDA approval in September 2013 for the 
first-line treatment of metastatic adenocarcinoma of the pancreas. 
 
Nanoliposomal irinotecan in combination with 5-FU was recently approved for patients with 
previously treated pancreatic cancer.  However, it is unknown if this combination is better than 5-
FU and irinotecan (FOLFIRI) as 5-FU was the comparator and there was no benefit in patients 
who previously received irinotecan so the value of this drug is questionable in FOLFIRINOX 
treated patients[1, 9].  Therapies for patients with metastatic pancreatic cancer are urgently needed.  
 
Novel approaches, such as immunotherapy, hold promise in this very difficult cancer.   
 
2.2. 
Dual Blockade of PD-1 and CXCR4 
 
 
 
 
 
 
  
 


 
8
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3. 
Dose Selection 
 
2.3.1.  Cemiplimab  
 
Cemiplimab is a PD-1 receptor blocking antibody.  The initial US approval was in September 2018 
for the treatment of patients with metastatic or locally advanced cutaneous squamous cell 
carcinoma who are not candidates for curative surgery or curative radiation.  The recommended 
dosage is 350mg as an intravenous infusion over 30 minutes every 3 weeks and is therefore, the 
dose and schedule selected for this study. 
 
2.3.2.  Plerixafor 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
2.4. 
Rationale 
 
 
 
 
 
 


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-
 
 
 
 
 
 
 
 
 


 
10
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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This study aims to combine plerixafor and cemiplimab to synergistically improve T cell activation, 
proliferation, and infiltration to combat immune evasion by tumors. This study will be an open 
label, phase II study to evaluate ORR using iRECIST in patients with metastatic previously-treated 
pancreatic adenocarcinoma. 
 
3. 
PATIENT SELECTION 
 
3.1. 
Eligibility Criteria 
 
3.1.1. Age ≥18 years. 
 
3.1.2. ECOG performance status of 0-1 (Appendix A). 
 
3.1.3. Have histologically- or cytologically-proven ductal adenocarcinoma of the 
pancreas.   


 
12
 
3.1.4. Have metastatic disease. 
 
3.1.5. Have documented radiographic disease progression at the time of study enrollment, 
after previous systemic chemotherapy given in a neoadjuvant, adjuvant, locally 
advanced or metastatic setting.  
 
3.1.6. Presence of at least one lesion with measurable disease as defined by 10 mm in 
longest diameter for a soft tissue lesions or 15 mm in short axis for a lymph node 
by RECIST 1.1. 
 
3.1.7. Patient’s acceptance to have a tumor biopsy of an accessible lesion at baseline and 
on treatment. 
 
 
 
3.1.8. Life expectancy of greater than 3 months. 
 
 
 
3.1.9. Adequate organ and marrow function as defined below: 
 
 
Leukocytes 
 
 
 
 
 
≥ 3,000/mcL 
 
Absolute neutrophil count 
 
≥ 1,000/mcL 
 
Platelets 
 
 
 
 
 
 
≥ 90 × 103/uL 
 
Hemoglobin   
 
 
 
 
≥ 8.0 g/dL 
 
Total bilirubin  
 
 
 
 
≤ 1.5 upper limit of normal (ULN) except 
subjects with Gilbert Syndrome, who can have 
total bilirubin < 3.0 mg/dL 
 
AST(SGOT) and ALT(SGPT ) 
≤3.0 × ULN 
 
Alkaline phosphatase  
 
 
≤5.0 × ULN  
 
Creatinine  
  
 
 
 
≤1.5 × ULN or creatinine clearance (CrCl) 
≥ 40 mL/min (if using the Cockcroft-Gault formula 
below): 
 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                              72 x serum creatinine in mg/dL 
 
    Male CrCl = (140 - age in years) x weight in kg x 1.00  
                     
 
 
 
 
72 x serum creatinine in mg/dL 
 
 
Albumin  
 
 
 
 
 
≥3.0 g/dL 
 
3.1.10. Women of childbearing potential (WOCBP) must have a negative serum pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]).  WOCBP is defined in Section 4.8. NOTE: If a patient has 
a positive or indeterminate serum or urine pregnancy test, then an ultrasound must 
be done to rule out pregnancy to enroll on trial. 
 


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- 
WOCBP must agree to follow instructions for method(s) of contraception from 
the time of enrollment for the duration of treatment with study drug(s) plus 5 
half-lives of study drug(s) plus 4 weeks (duration of ovulatory cycle) for a total 
of 5 months post treatment completion. 
 
- 
Men who are sexually active with WOCBP must agree to follow instructions 
for method(s) of contraception for the duration of treatment with study drug(s) 
plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for 
a total of 7 months post-treatment completion. 
 
- 
At least one barrier method of contraception must be employed by all sexually 
active patients (male and female), regardless of other methods, to prevent the 
transfer of body fluids. 
 
3.1.11. Ability to understand and willingness to sign a written informed consent document. 
 
3.2. 
Exclusion Criteria 
 
 3.2.1. Patient has a known history or evidence of brain metastases. 
 
3.2.2.  Patient who has had chemotherapy, radiation, or biological cancer therapy within 
14 days prior to the first dose of study drug. 
 
3.2.3. Patient has received an investigational agent or used an investigational device 
within 28 days of the first dose of study drug. 
 
3.2.4.  Patient is expected to require any other form of systemic or localized antineoplastic 
therapy while on study. 
 
3.2.5. Patients who have had surgery within 28 days of dosing of investigational agent, 
excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, 
and biliary stent placement. 
 
3.2.6. Patients who have received any prophylactic vaccine within 14 days of first dose 
of study drug or received a live vaccine within 30 days of planned start of study 
therapy. 
 
3.2.7. Patients with a history of prior treatment with an anti-CXCR4 agent. 
  
3.2.8.  Currently using any chronic systemic steroids (at doses exceeding 10 mg daily of 
prednisone equivalent) or any other form of immunosuppressive therapy (steroid 
premedication for contrast is allowed).  
 
3.2.9.  Patients receiving growth factors including, but not limited to, granulocyte-colony 
stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug 
administration. Use of such agents while on study is also prohibited.  


 
14
 
3.2.10. History of severe hypersensitivity reaction to any monoclonal antibody. Exceptions 
may be approved by Protocol Chair if the patient has subsequently tolerated an 
antibody. 
 
3.2.11. Evidence of clinical or radiographic ascites. Trace or small amounts of radiographic 
ascites may be approved by the Protocol Chair. 
 
3.2.12. History of clinically significant and/or malignant pleural effusion. 
 
3.2.13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
symptomatic cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.2.14. Subjects with active autoimmune disease. Subjects with Graves or Hashimoto’s 
disease, vitiligo, type I diabetes mellitus, psoriasis or other conditions not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll. Subjects with autoimmune conditions requiring 
systemic treatment in the past may be approved by the Protocol Chair. 
 
3.2.15. Presence of any tissue or organ allograft, regardless of need for 
immunosuppression, including corneal allograft. Exceptions can be approved by 
the Protocol Chair if loss of the graft is not a clinical concern.  Patients with a 
history of allogeneic hematopoietic stem cell transplant will be excluded. 
 
3.2.16. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue 
must have resolved to grade 1 (National Cancer Institute Common Terminology 
Criteria for Adverse Events [CTCAE], version 5) or baseline before administration 
of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which 
are not expected to resolve and result in long-lasting sequelae, such as neuropathy 
after chemotherapy, are permitted to enroll. 
 
3.2.17. Have received a diagnosis of human immunodeficiency virus (HIV), hepatitis B 
(Hep B sAg negative permitted) or hepatitis C (patients who are hepatitis C 
antibody positive may be enrolled if they are confirmed with negative viral load at 
screening) 
 
3.2.18. Patient has a pulse oximetry of <92% on room air. 
 
3.2.19. Patient is on supplemental home oxygen. 
 
3.2.20.  Patient has clinically significant heart disease (such as uncontrolled angina, 
myocardial infarction within the last 3 months or congestive heart failure of New 
York Heart Association III or IV). 
 


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3.2.21. Patient is, at the time of signing informed consent, a regular user (including 
“recreational use”) of any illicit drugs or other substance abuse (including alcohol) 
that could potentially interfere with adherence to study procedures or requirements. 
 
3.2.22. Patient is unwilling or unable to follow the study schedule for any reason. 
 
 
3.2.23. Patient is pregnant or breastfeeding. 
 
3.2.24. Have rapidly progressing disease, as judged by the investigator (e.g., rapid 
progression through prior treatment[s]). 
 
3.2.25. History of significant, recurrent, unexplained postural hypotension in the last 6 
months. 
 
3.3. 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. 
TREATMENT PLAN 
 
4.1. 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Appropriate dosing delays are described in 
Section 5. No investigational or commercial agents or therapies other than those described below 
in Table 1 may be administered with the intent to treat the patient’s malignancy. 
 
Table 1: Regimen Description 
 
REGIMEN DESCRIPTION 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Cemiplimab 
No prophylactic 
pre-medication 
will be given 
unless indicated 
by previous 
experience in an 
individual 
subject per 
Section 4.2 
350mg 
IV infusion 
over 30  
(+/-15) 
min* 
Day 1 
21 days 
Plerixafor 
80mcg/kg/hr 
(1920mcg/kg/24hrs) 
Continuous 
IV infusion 
over 7 
days** 
Days 1-7 
21 days 
*Infusion times are approximate and may be adjusted based on subject tolerability. 
** Plerixafor formulation for infusion is stable for 5 days at room temperature. Therefore, patients 
will return to clinic on day 4 to exchange the infusion bag and on day 8 to discontinue their 
plerixafor infusion. The bag exchange on Day 4 should occur within 1 hour of completion of the 
first infusion bag.  
 


 
16
Subjects should be observed for a minimum of 30 minutes between the administration of 
cemiplimab and plerixafor. 
 
Please see Section 5.2 for guidance regarding dosing delays. 
 
Antiemetic medications should not be routinely administered prior to dosing of drugs. See Section 
4.2.1 for subsequent premedication recommendations following an infusion reaction.  
 
4.2. 
General Concomitant Medication and Supportive Care Guidelines 
 
Cemiplimab and plerixafor can cause hypersensitivity reactions. Subjects should be closely 
monitored for potential AEs during infusion and potential AEs throughout the study. 
 
4.2.1. Infusion Reactions 
 
If an infusion reaction were to occur, it might manifest with fever, chills, rigors, headache, 
rash, pruritus, arthralgias, hypo- or hypertension, bronchospasm, or other allergic-like 
reactions. All grade 3 or 4 infusion reactions should be reported to the Protocol Chair and 
reported as an SAE if criteria are met. Infusion reactions should be graded according to 
CTCAE (version 5.0) guidelines.  
 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate: 
 
For grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
 
Remain at bedside and monitor subject until recovery from symptoms. The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at 
least 30 minutes before additional co-administrations. 
 
For grade 2 symptoms (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours): 
 
Stop the infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
or bronchodilator therapy may also be administered as appropriate. If the infusion 
is interrupted, restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may 
be increased to 100% of the original infusion rate. Monitor subject closely. If 
symptoms recur then no further study drug will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the 


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subject until resolution of symptoms. The amount of study drug infused must be 
recorded on the case report form (CRF).  
 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg 
should be administered at least 30 minutes before study drug infusions. If 
necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.  
 
For grade 3 or grade 4 symptoms (severe reaction, grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [e.g., renal impairment, pulmonary infiltrates]; grade 4: (life threatening; pressor 
or ventilator support indicated): 
 
Immediately discontinue infusion of study drug. Begin an IV infusion of normal 
saline, and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 
to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 
mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. Subject should 
be monitored until the investigator is comfortable that the symptoms will not recur. 
All study drugs will be permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery from symptoms.  
 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids). 
 
4.2.2. Cemiplimab and Plerixafor-Related Adverse Events 
 
4.2.2.1 Cemiplimab Related Adverse Events 
 
Blocking PD-1 may permit the emergence of auto-reactive T cells and resultant clinical 
autoimmunity. Rash/pruritus, diarrhea/colitis, pneumonitis, hepatitis, and hypothyroidism 
were drug-related, presumptive autoimmune events noted in previous anti-PD-1 studies.  
 
For the purposes of this study, a cemiplimab-related AE is defined as an AE of unknown 
etiology, associated with drug exposure and is consistent with its known toxicity profile. 
Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic 
causes. Serological, immunological, and histological (biopsy) data should be used to 
support the diagnosis of an immune-mediated toxicity. Suspected AEs must be documented 
on an AE or SAE CRF. Identification and treatment of cemiplimab-related AEs can be 
found in the NCCN’s guidelines for the management of immunotherapy-related toxicities. 
Additional guidance can be found in the cemiplimab Investigator’s Brochures (IB).  
 


 
18
Subjects who experience a grade 3 or higher related AE should be discussed with the 
Protocol Chair immediately.  
 
4.2.2.2 Plerixafor Related Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
4.3. 
Prohibited and/or Restricted Treatments 
 
The following medications are prohibited during the study: 
 
  Immunosuppressive agents unless they are utilized to treat an AE or as specified in 
Sections 4.2 and 4.5. 
 Concurrent administration of any anticancer therapies (investigational or approved) 
with the exception of subjects in the survival period of the study. 
 Use of growth factors unless prior discussion and agreement with the Protocol Chair. 
  Use of allergen hyposensitization therapy 
 
Palliative radiotherapy is permitted only under certain conditions as described in Section 4.5. 
 


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4.4. 
Other Restrictions and Precautions 
Any vaccination containing attenuated or inactivated virus may be permitted if clinically indicated. 
However, this must be discussed and documented with the Protocol Chair prior to administration 
and may require a study drug washout period prior to and after administration of the vaccine. 
Inactivated influenza vaccination will be permitted on study without restriction.  
It is the local imaging facility’s responsibility to determine, based on subject attributes (e.g., 
allergy history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each subject. Imaging contraindications and contrast risks should be considered in this 
assessment. Subjects with renal insufficiency should be assessed as to whether or not they should 
receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, subjects 
with severe renal insufficiency (i.e., estimated glomerular filtration rate (eGFR) < 30 
mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis.  
4.5. 
Permitted Therapy 
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Immunosuppressive agents and the use of 
systemic corticosteroids are permitted in the context of treating AEs, prophylaxis prior to a 
diagnostic procedure (e.g., contrast MRI/CT scans) or as specified in Section 4.2. A brief course 
of corticosteroids for prophylaxis (e.g., contrast dye allergy) is permitted.  
Subjects may continue to receive hormone replacement therapy (HRT).  
Palliative and supportive care for disease-related symptoms may be offered to all subjects on the 
trial.  
The potential for overlapping toxicities with radiotherapy and cemiplimab and plerixafor is 
currently not known. Therefore, palliative radiotherapy is not recommended while receiving any 
of these drugs, alone or in combination. If palliative radiotherapy in short courses and for isolated 
fields is required to control symptoms, then drug administration should be withheld, if possible, 
for at least 1 week before radiation and for at least 1 week after its completion. Subjects should be 
closely monitored for any potential toxicity during and after receiving radiotherapy. Prior to 
resuming study drug treatment, radiotherapy-related AEs should resolve to Grade 1 or baseline 
and subjects must meet relevant dosing eligibility criteria The Protocol Chair must be consulted 
prior to re-initiating treatment in a subject with a dosing interruption lasting > 6 weeks after the 
last dose.  
Details of palliative radiotherapy should be documented in the source records and electronic case 
report form (eCRF). Details in the source records should include: dates of treatment, anatomical 
site, dose administered and fractionation schedule, and AEs. Symptoms requiring palliative 
radiotherapy should be evaluated for objective evidence of disease progression. Subjects receiving 
palliative radiation of target lesions will have the evaluation of ORR just prior to radiotherapy but 
such subjects will no longer be evaluable for determination of response subsequent to the date 
palliative radiation occurs.  


 
20
For subjects who need to undergo elective surgery (not tumor-related) during the study, it is 
recommended to hold study drug(s) for at least 2 weeks before and 2 weeks after surgery, or until 
the subject recovers from the procedure, whichever is longer. Prior to resuming study drug 
treatment, surgically-related AEs should resolve to Grade 1 or baseline and subjects must meet 
relevant dosing eligibility criteria. The Protocol Chair must be consulted prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 6 weeks after the last dose.  
4.6. 
Definition of an Overdose for this Protocol 
 
Overdose of cemiplimab or plerixafor is defined as: 
 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Appropriate supportive treatment should be 
provided if clinically indicated. 
 
All reports of overdose (with and without an AE) must be reported within 24 hours to the Protocol 
Chair and Sanofi as an SAE per Section 6. 
4.7. Unacceptable Toxicity 
 
Unacceptable toxicities are defined as any adverse event requiring permanent discontinuation per 
Section 4.10.2 (exceptions for permanent discontinuation must be approved by the Protocol 
Chair). 
 
If more than 1 of the first 6 patients experiences an unacceptable toxicity within the first cycle, 
then enrollment will be halted, and the overall risk-benefit ratio of the study will be reconsidered. 
At any time thereafter, if more than 33% of patients are observed to experience unacceptable 
toxicity within the first cycle, enrollment will be suspended until further review and consideration 
by the Protocol Chair. There will be no dose reductions for cemiplimab or plerixafor. 
 
4.8. 
WOCBP, Contraception, Use in Pregnancy, Use in Nursing 
 
4.8.1. Definition of Women of Childbearing Potential 
 
WOCBP is defined as any female who has experienced menarche and who has not 
undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not 
postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 
45 in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a documented serum follicle stimulating hormone (FSH) 
level > 40mIU/mL to confirm menopause.  
 
Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The 
duration of the washout period below are suggested guidelines and the investigators should 
use their judgment in checking serum FSH levels.  
 


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 1 week minimum for vaginal hormonal products (e.g., rings, creams, gels)  
 4 weeks minimum for transdermal products  
 8 week minimum for oral products  
 
Other parenteral products may require washout periods as long as 6 months. If the serum 
FSH level is > 40 mlU/mL at any time during the washout period, the woman can 
considered postmenopausal. 
 
4.8.2. Contraception 
 
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 24 weeks after the end 
of study treatment.* 
 
Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly.a  
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb  
 oral  
 intravaginal  
 transdermal  
 Progestogen-only hormonal contraception associated with inhibition of ovulationb  
 oral  
 injectable  
Highly Effective Methods That Are User Independent  
 Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b 
 Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c 
 Intrauterine device (IUD)c 
 Bilateral tubal occlusion 
 Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  


 
22
 Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
 It is not necessary to use any other method of contraception when complete abstinence is 
elected.  
 WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 9.  
 Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence  
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants 
participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the 
efficacy of the contraceptive method.  Hormonal contraception is permissible only when there is 
sufficient evidence that the IMP and other study medications will not alter hormonal exposures such 
that contraception would be ineffective or result in increased exposures that could be potentially 
hazardous.  In this case, alternative methods of contraception should be utilized.  
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of 
contraception in the absence of definitive drug interaction studies when hormone exposures from 
intrauterine devices do not alter contraception effectiveness 
 
Unacceptable Methods of Contraception* 
 Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously 
 Diaphragm with spermicide 
 Cervical cap with spermicide 
 Vaginal Sponge with spermicide 
 Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
 Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 Withdrawal (coitus interruptus). 
 Spermicide only 
 Lactation amenorrhea method (LAM) 
 
* Local laws and regulations may require use of alternative and/or additional 
contraception methods. 


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CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH 
PARTNER(S) OF CHILD BEARING POTENTIAL. 
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to the following during the treatment and until the end of relevant systemic 
exposure. 
 Inform any and all partner(s) of their participation in a clinical drug study and the need 
to comply with contraception instructions as directed by the investigator. 
 Male participants are required to use a condom for study duration and until end of 
relevant systemic exposure defined as 33 weeks after the end of study treatment. 
 Female partners of males participating in the study to consider use of effective methods 
of contraception until the end of relevant systemic exposure, defined as 7 months after 
the end of treatment in the male participant. 
 Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile vaginal intercourse or use a male condom during each episode of 
penile penetration during the treatment and until 33 weeks after the end of study 
treatment.  
Refrain from donating sperm for the duration of the study treatment and until 7 months 
after the end of study treatment. 
 
4.8.3. Use in Pregnancy 
 
The investigational agents used in this protocol may have adverse effects on a fetus; 
therefore, women with a positive pregnancy test at screening will not be eligible for 
enrollment.  If a subject inadvertently becomes pregnant while on treatment, the subject 
will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.   
 
Pregnancy in female subjects throughout the study or within 24 weeks of completing 
treatment as well as any pregnancy in partners of male subjects throughout the study or 
within 33 weeks of completing the study should be reported initially as a serious adverse 
event (see SAE reporting procedures in Section 6.5.1 and 6.5.4) by the investigator within 
24 hours of learning of its occurrence. Pregnancy information must be reported on the 
Pregnancy Form. 
 
Protocol required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated.  
 
Follow-up information regarding the course of the pregnancy, including any voluntary or 
spontaneous termination, perinatal and neonatal outcome and where applicable, offspring 
information must be reported on the Pregnancy Follow-up Form. Pregnancy outcomes 
must also be collected for the female partners of any males in this trial. Consent to report 
information regarding these pregnancy outcomes should be obtained from the female 
partner.  


 
24
 
4.8.4. Use in Nursing Women 
 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment. 
 
4.9. 
Duration of Therapy 
 
Subjects who are clinically stable and meet dosing requirements (per Section 5.2) may continue 
to receive treatment for up to a maximum of 2 years.  
 
4.10. Criteria for Removal from Treatment 
 
The reason for study removal and the date the subject was removed will be documented in the 
CRF. A subject must be discontinued from the trial for any of the following reasons: 
 
 The subject or legal representative (such as parent or legal guardian) withdraws 
consent. 
 
A subject must be discontinued from treatment (but may continue to be monitored in the post-
treatment follow-up portion of the trial) for any of the following reasons: 
 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment, 
 Disease progression as defined in Section 4.10.1.  If there are no signs of disease 
stabilization after 18 weeks of therapy, subjects should be discontinued, 
 Intercurrent illness that prevents further administration of treatment, 
 Severe or life-threatening cemiplimab- or plerixafor-related AE(s) (see Section 4.10.2), 
 Need for >2 dose delays due to the same related toxicity as per the dose delay guidelines 
(see Section 5.2) 
 If in the opinion of the Investigator, a change or temporal or permanent discontinuation 
of therapy would be in the best interest of the patient, 
 Noncompliance with trial treatment or procedure requirements, 
 Patient is lost to follow-up, 
 Patient becomes pregnant, or 
 Completed 24 months of treatment with cemiplimab and plerixafor. Note: 24 months 
of study medication is calculated from the date of the first dose. 
 
4.10.1. Disease Progression 
 
Immunotherapy is expected to trigger immune-mediated responses, which require 
activation of the immune system prior to the observation of clinical responses. Such 
immune activation may take weeks to months to be evident. Some subjects may have 
objective volume increase of tumor lesions or other disease parameters within weeks 
following the start of immunotherapy. Such subjects may not have had sufficient time to 


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25
develop the required immune activation or, in some subjects, tumor volume or other disease 
parameter increases may represent infiltration of lymphocytes into the original tumor. In 
conventional studies, such tumor volume or relevant laboratory parameter increases during 
the first 2-4 months of the study would constitute disease progression and lead to 
discontinuation of imaging to detect response, thus disregarding the potential for 
subsequent immune-mediated clinical response [11]. 
 
Subjects will be permitted to continue with treatment beyond RECIST 1.1 defined PD as 
long as they meet the following criteria: 
 
Investigator-assessed clinical benefit, and 
 
Subject is tolerating study drug. 
 
If there are no signs of disease stabilization after 18 weeks of therapy, subjects should be 
discontinued. 
 
All decisions to continue treatment beyond PD must be discussed with the Protocol Chair  
and documented in the study records. 
 
Tumor assessments will be made using RECIST 1.1 and iRECIST (Appendix B and C).  
 
4.10.2. Cemiplimab- and Plerixafor-Related Adverse Events 
 
Permanent discontinuation of all study treatment should be considered for any of the 
following (exceptions for permanent discontinuation must be approved by the Protocol 
Chair): 
1. Severe or life-threatening related AEs, including, but not limited to, any of the 
following (the Protocol Chair must be notified in the event of these AEs): 
 Any grade 2 treatment-related uveitis, eye pain, or blurred vision that does not 
respond to topical therapy and does not improve to ≤ Grade 1 severity within 
the re-treatment period OR requires systemic treatment 
 
 Any grade 3 non-skin, drug-related AE lasting > 7 days, with the following 
exceptions: 
 
 Grade 3 treatment-related uveitis, pneumonitis, bronchospasm, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation 
 
 Grade 3 treatment-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
 
 Grade 3 treatment-related laboratory abnormalities do not require treatment 
discontinuation except: 
 


 
26
o Grade 3 treatment-related thrombocytopenia > 7 days OR that is 
associated with bleeding requires discontinuation 
 
o Any treatment-related liver function test (LFT) abnormality that 
meets the following criteria require discontinuation: 
 
ALT or AST > 8 x ULN, regardless of duration, or 
 
ALT or AST > 5 x and ≤ 8 x ULN, that fails to return to ≤ 
Grade 1 within 2 weeks despite medical intervention, or 
 
Total bilirubin > 5 × ULN, or 
 
Potential drug-induced liver injury (DILI) event (Section 
6.5.5) 
 
 Any grade 4 treatment-related AE or laboratory abnormality, except for the 
following events which do not require discontinuation: 
 
 Grade 4 neutropenia ≤ 7 days 
 
 Grade 4 lymphopenia and leukopenia. 
 
 Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations. 
 
 Isolated grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset.  
 
 Grade 4 treatment-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require discontinuation after 
discussion with and approval from the Protocol Chair. 
 
 Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
 Dosing interruptions to allow for prolonged steroid tapers to manage drug-
related adverse events are allowed. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the Protocol Chair must 
be consulted. Tumor assessments should continue as per protocol even if 
dosing is interrupted. Periodic study visits to assess safety and laboratory 
studies should also continue every 6 weeks or more frequently if clinically 
indicated during such dosing delays. 
 
 Dosing interruptions > 6 weeks that occur for non-drug-related reasons may 
be allowed if approved by the Protocol Chair. Prior to re-initiating treatment 
in a subject with a dosing interruption lasting > 6 weeks, the Protocol Chair 


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must be consulted. Tumor assessments should continue as per protocol even 
if dosing is interrupted. Periodic study visits to assess safety and laboratory 
studies should also continue every 6 weeks or more frequently if clinically 
indicated during such dosing delays. 
 
 Any AE, laboratory abnormality, or intercurrent illness which, in the judgment 
of the Investigator, presents a substantial clinical risk to the subject with 
continued dosing.  
 
In order to standardize the management of irAEs for all subjects, treatment management 
algorithms can be found in the NCCN’s guidelines for the management of immunotherapy-
related toxicities. Additional AE treatment management guidance included in the IBs might 
be considered for individual cases. 
 
4.11. End of Treatment (EOT) 
 
All subjects will return to the study site 30 days (± 7 days) after the last dose of study drug (or 
within 7 days prior to initiation of a new anti-cancer treatment, whichever comes first) for an 
EOT evaluation. Procedures and assessments performed at this visit and beyond should follow 
the respective guidelines described in Sections 4.12 and 9 as appropriate.  
 
4.12. Duration of Follow Up 
 
4.12.1. Safety Follow-up 
 
Subjects who discontinue treatment should be contacted by telephone or email at 100 days 
(+ 14 day reporting window) from their last dose of study drug or within 7 days before 
initiation of a new antineoplastic treatment (whichever comes first) to assess for treatment 
related toxicities. In addition, all SAEs occurring during this time should be reported as 
well.  
 
Subjects who are discontinued from the study treatment due to an unacceptable drug-
related AE will be monitored for safety until the resolution of the AE to ≤ grade 1 or 
stabilization or until initiation of a new therapy for their cancer, whichever occurs first. 
 
4.12.2. Clinical Follow-up 
 
All enrolled subjects who discontinue treatment without disease progression will enter the 
clinical follow-up portion of the trial. Subjects will begin the clinical follow-up period after 
they complete the EOT visit. Clinical follow-up visits will occur every 12 weeks (± 2 
weeks) until: 1) start of a new antineoplastic therapy (information of the new cancer therapy 
will be collected), 2) disease progression, 3) death, 4) withdrawal of consent, or 5) study 
closure, whichever occurs first. Refer to Section 9 for the schedule of assessments that 
should be performed at each visit. After disease progression or start of a new antineoplastic 
therapy, subjects will enter the survival follow-up portion of the trial (Section 4.12.3).  
 


 
28
4.12.3. Survival Follow-up  
 
Subjects who discontinue treatment and have disease progression will enter the survival 
follow-up portion of the trial. Subjects should be contacted every 12 weeks (± 2 weeks) to 
monitor overall survival. Information of other cancer therapies after discontinuation from 
the study treatment will be collected as well.  
 
5. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1. 
Dose Modifications 
 
Subjects will be monitored continuously for AEs while on study drug. Subjects will be instructed 
to notify their physician immediately for any and all AEs. Dose escalations or reductions of 
cemiplimab or plerixafor will not be allowed.  
 
5.2. 
Dose Delays 
 
In some cases, the natural history of select AEs associated with immunotherapy can differ from 
and be more severe than AEs caused by other therapeutic classes. Early recognition and 
management may mitigate severe toxicity. 
 
Guidance for Investigators is provided in the current cemiplimab and plerixafor Investigator’s 
Brochures. Additionally, management algorithms have been developed to assist Investigators with 
select toxicities and can be found in the NCCN’s guidelines for the management of 
immunotherapy-related toxicities.  
 
Subjects who experience the following must have all study drugs held: 
 
 Select drug-related AEs and drug-related laboratory abnormalities: 
o Grade ≥ 2 pneumonitis 
o AST/ALT > 3 x ULN 
o Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total 
bilirubin < 3.0 mg/dL) 
o Creatinine > 1.5 x ULN 
o Grade ≥3 diarrhea or colitis 
o Grade ≥ 2 neurological AE 
 Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study drug. 
 
Subjects not meeting guidelines for permanent discontinuation will be permitted to resume 
therapy when the treatment-related AE(s) resolve to grade ≤1 or baseline value, with the 
following exceptions: 
 
 If the toxicity resolves to ≤ Grade 1 or baseline > 6 weeks after last dose, but the subject 
does not otherwise meet criteria for permanent discontinuation, and the Investigator 


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believes that the subject is deriving clinical benefit, then the subject may be eligible to 
resume the study drugs following the approval of the Protocol Chair. 
 Subjects with grade 4 drug-related amylase and/or lipase increase that is not associated 
with symptoms or clinical manifestations of pancreatitis can continue on therapy. 
 Subjects may resume treatment in the presence of Grade 2 fatigue. 
 Subjects with baseline normal or grade 1 AST, ALT or total bilirubin who require dose 
delays for reasons other than a drug-related hepatic event may resumed treatment in the 
presence of grade 2 AST, ALT or total bilirubin elevation. 
 Subjects who require dose delays for drug-related elevations in AST, ALT, or total 
bilirubin may resume treatment when these values have returned to their baseline 
CTCAE grade or normal, provided the criteria for permanent discontinuation are not 
met. 
 Treatment-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment. 
 
Subjects eligible to resume study drug will resume study drug at the treatment visit following 
their last received study drug dose.  
 
The on treatment tumor assessments (i.e., CT/MRI, positron emission tomography [PET], etc.) 
will continue on an every 9-week schedule relative to the subject’s first dose regardless of any 
treatment delay incurred. Subjects who are required to permanently discontinue both study 
drugs are listed in Section 4.10. 
 
6. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
This study will use the descriptions and grading scales found in the revised CTCAE version 5.0 
for AE reporting.   
 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected, recorded, and followed as appropriate.  
 
6.1. 
Definitions 
 
6.1.1. Adverse Event 
 
An AE is defined as any undesirable sign, symptom or medical condition occurring after 
starting the study drug (or therapy) even if the event is not considered to be related to the 
study. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram). Medical conditions/diseases present before 
starting the study treatment are only considered AEs if they worsen after starting the study 
treatment (any procedures specified in the protocol). New medical conditions / diseases 
occurring before starting the study treatment but after signing the informed consent form 
will not be recorded as AEs. Additionally, expected progression of the disease being 
studied will not be recorded as an adverse event.  


 
30
 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will 
be recorded as pre-treatment signs and symptoms. After study treatment administration, all 
grade 3 and 4 clinical laboratory results that represent an increase in severity from baseline 
will be reported as AEs. A grade 1 or 2 clinical laboratory abnormality should be reported 
as an AE only if it is considered clinically significant by the investigator (induce clinical 
signs or symptoms or require corrective therapy), meets the definition of an SAE, or 
requires the participant to have study drug discontinued or interrupted. It is expected that 
wherever possible, the clinical rather than laboratory term would be used by the reporting 
investigator (e.g., anemia versus low hemoglobin value). 
 
6.1.2. Serious Adverse Event 
 
A SAE is an undesirable sign, symptom or medical condition which:  
• 
Results in death  
• 
Is life threatening (defined as an event in which the subject 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 
(see note below for exceptions) for >24 hours 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth 
defects must also be reported on the Pregnancy Form)  
• 
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.) 
• 
Potential drug induced liver injury (DILI) is also considered an important medical 
event.  
• 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) 
via the study drug is an SAE. 
• 
Is a new cancer (that is not a condition of the study) 
• 
Is associated with an overdose 
• 
Is a pregnancy or pregnancy outcome of spontaneous abortion, missed abortion, 
benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage, or stillbirth. 
 
Events not considered to be SAEs are hospitalizations for:  
• 
a visit to the emergency room or other hospital department <24 hours, that does not 
result in admission (unless considered an important medical or life-threatening 
event) 


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31
• 
Admissions as per protocol for a planned medical/surgical procedure or to facilitate 
a procedure 
• 
Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)  
• 
Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study. Appropriate documentation is required in 
these cases.  
• 
Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative). 
 
6.1.3. Adverse Event of Special Interest (AESI) 
 
An adverse event of special interest (AESI) is an adverse event (serious or non-serious) of 
scientific and medical concern specific to the investigational product, for which ongoing 
monitoring and rapid communication by the Investigator to the Protocol Chair and Sanofi 
may be appropriate. Such events may require further investigation in order to characterize 
and understand them.  
 
6.2. 
Relationship 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
 
 No (unrelated, not related, no relation):  The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.  
 
 Yes (related): The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal relationship 
and no other cause (concomitant drugs, therapies, complications, etc.) can be identified.  
 
The following factors should also be considered:  
 
 The temporal sequence from study drug administration - The event should occur after 
the study drug is given. The length of time from study drug exposure to event should 
be evaluated in the clinical context of the event.  
 Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have.  
 Concomitant medication - The other medications the subject is taking or the treatment 
the subject receives should be examined to determine whether any of them might be 
recognized to cause the event in question.  
 Known response pattern for this class of study drug - Clinical and/or preclinical data 
may indicate whether a particular response is likely to be a class effect.  


 
32
 Exposure to physical and/or mental stresses - The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.  
 The pharmacology and pharmacokinetics of the study drug - The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug 
should be considered.  
 
Assessment of Grade: 
 
The investigator will make an assessment of grade for each AE and SAE reported during the study, 
which will be recorded in the CRF. The assessment will be based on the National Cancer Institute’s 
CTCAE (Version 5.0) and graded as shown below: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
 
Any AE that changes in grade during its course will be recorded in the CRF at the highest level 
experience by the subject. 
 
6.3. 
Expectedness 
 
Unexpected AE: An AE, which varies in nature, intensity or frequency from information on the 
investigational drug/agent provided in the product IB, package insert or safety reports. Any AE 
that is not included in the IB, package insert, safety reports or informed consent is considered 
“unexpected”. An expected AE with a fatal outcome should be considered unexpected unless the 
IB specifically states that the AE might be associated with a fatal outcome. 
 
Expected (known) AE: An AE, which has been reported in the IB, package insert or safety reports. 
An AE is considered “expected”, only if it is included in the IB document as a risk. 
 
6.4. 
Handling of Expedited Safety Reports 
 
In accordance with local regulations, Sanofi will notify investigators of all SAEs that are 
unexpected (i.e., not previously described in the IB), and related to plerixafor and cemiplimab. An 
event meeting these criteria is termed a Suspected, Unexpected Serious Adverse Reaction 
(SUSAR). Investigator notification of these events will be in the form of a SUSAR Report that is 
to be e-mailed to the investigators and the study coordinators. Upon receiving such notices, the 
investigator must review and retain the notice with the IB and where required by local regulations, 
the investigator will submit the SUSAR to the appropriate IRB. The investigator and IRB will 


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33
determine if the informed consent requires revision. The investigator should also comply with the 
IRB procedures for reporting any other safety information. 
 
6.5. 
Reporting 
 
6.5.1. Adverse Events (AEs) and Serious Adverse Events (SAEs) 
 
All AEs (both expected and unexpected) occurring from the first dose of study drug will 
be captured on the appropriate study-specific case report forms (CRFs).  
 
All AEs (both related and unrelated) will be captured on the appropriate study-specific 
CRFs. All AEs experienced by subjects will be collected and reported from the first dose 
of the investigational agent, throughout the study, and will be followed for 28 days after 
last dose of study drug unless related to the investigational agent. 
 
Subjects who experience a grade 3 or higher cemiplimab or plerixafor-related AE should 
be discussed with the Protocol Chair.  
 
Report AEs to the Protocol Chair within 24 hours once identified as an unacceptable 
toxicity (defined in Section 4.7).   
 
 
Dung Le (Protocol Chair): 
 
 
Report AESIs to the Protocol Chair and Sanofi within 24 hours once identified 
(defined in Section 6.1.3) using the form found in Appendix E.   
 
 
Dung Le (Protocol Chair): 
 
 
Sanofi:  
 
 
 
 
Regeneron: 
 
 
 
 
All SAEs (including deaths) occurring from the first dose of study drug, throughout the 
study, and 100 days (+14 day reporting window) after the last dose of study drug or before 
initiation of a new antineoplastic treatment (whichever comes first) must be reported. All 
SAEs that the investigator considers related to the study drug occurring after the follow-up 
periods must be reported.  
 
SAEs will be reported promptly to the Protocol Chair and Sanofi within 24 hours of 
recognition of the adverse event using the form found in Appendix D.  If this falls on a 
weekend or holiday, an email notification is acceptable but must be followed by an SAE 
reporting form on the next business day. 
 
SAE reports and any other relevant safety information are to be sent to:  
 
 
Dung Le (Protocol Chair): 
 
 
Sanofi:  
 
 
 
 
Regeneron: 
 
 
 


 
34
 
6.5.2. Follow-up of Adverse Events and Serious Adverse Events 
 
After the initial AE or SAE report, the investigator is required to proactively follow each 
subject and provide further information to the safety department concerning the subject’s 
condition. 
 
All AE(s) and SAE(s) will be followed until: 
• 
Resolution 
• 
The condition stabilizes 
• 
The event is otherwise explained 
• 
The subject is lost to follow-up 
• 
Death 
 
As soon as relevant information is available, a follow-up SAE report will be submitted to 
the Protocol Chair and Sanofi. 
 
6.5.3. Reconciliation of SAEs 
 
The Principal Investigator will reconcile the clinical database SAE cases (case level only) 
transmitted to the Protocol Chair, Sanofi 
 
 
 Frequency of reconciliation should be 
approximately every 3 months and prior to the database lock or final data summary. Sanofi 
will email, upon request from the Principal Investigator (or representative), the 
reconciliation report. Requests for reconciliation should be sent to 
 The data elements listed 
on the Sanofi reconciliation report will be used for case identification purposes. If the 
Principal Investigator determines a case was not transmitted to the Protocol Chair and 
Sanofi, the case should be sent immediately to the Protocol Chair and Sanofi. 
 
6.5.4. Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as SAEs.  
 
6.5.5. Potential Drug-Induced Liver Injury (DILI) 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event.  All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs under the seriousness 
category checked as ‘other medically important event’. Potential drug induced liver injury 
is defined as: 
 
1) ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 


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35
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
6.5.6. Pregnancy Reporting 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial or within 24 weeks following 
cessation of the study drugs, or pregnancy of a partner of a male subject within 33 weeks of 
cessation of the study drugs, must be reported by the investigator using the Pregnancy 
Surveillance Form. All subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported to the 
Protocol Chair and Sanofi. 
Any SAE occurring during pregnancy (pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth) must be recorded on the SAE report form and submitted to the 
Protocol Chair and Sanofi.   
 
6.5.7. Institutional Review Board (IRB) 
 
SAEs will be reported to the IRB per institutional guidelines. Follow-up information will 
be submitted to the IRB as soon as relevant information is available. 
 
7. 
PHARMACEUTICAL INFORMATION 
 
Detailed instructions will be provided in the pharmacy manual. 
 
7.1. 
Cemiplimab 
 
7.1.1. Agent Accountability 
 
The Protocol Chair or the Protocol Chair’s representative shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations.  
At the end of the study period, Sanofi will not continue to supply study drug to 
subjects/investigators unless the Protocol Chair chooses to extend their study. The 
investigator is responsible to ensure that the subject receives appropriate standard of care 


 
36
or other appropriate treatment in the independent medical judgement of the Investigator to 
treat the condition under study. 
 
7.1.2. Mode of Action 
 
Cemiplimab is human monoclonal immunoglobulin (Ig) antibody that binds to the PD-1 
cell surface membrane receptor, a negative regulatory molecule expressed by activated T 
and B lymphocytes. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T cell responses to both foreign antigens as well as 
self-antigens. 
 
7.1.3. Description 
 
 
   
 
 
 
 
  
 
7.1.4. Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.  
7.1.5. Preparation 
 
 
 
 
 
 
7.1.6. Storage 
 
 
 
 
 
 
 
  
 
 
 
7.1.7. Stability 
 
 
 


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37
 
  
 
7.1.8. Route of Administration 
 
 
 
 
 
 
 
7.1.9. Subject Care Implications 
 
 
 
 
 
 
 
 
 
 
7.1.10. Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Sanofi or designee, the amount dispensed to, and returned by the subjects 
and the amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 
7.2. 
Plerixafor 
 
7.2.1. Agent Accountability 
 
The Protocol Chair or the Protocol Chair’s representative shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations. 
 
At the end of the study period, Sanofi will not continue to supply study drug to 
subjects/investigators unless the Protocol Chair chooses to extend their study. The 
investigator is responsible to ensure that the subject receives appropriate standard of care 


 
38
or other appropriate treatment in the independent medical judgement of the Investigator to 
treat the condition under study. 
 
7.2.2. Mode of Action 
 
Plerixafor is approved by the US FDA in combination with granulocyte-colony stimulating 
factor (G-CSF) to enhance mobilization of hematopoietic stem cells to the peripheral blood 
for collection and subsequent autologous transplantation in adult patients. Plerixafor is a 
bicyclam derivative, a selective reversible antagonist of CXCR4 chemokine receptor and 
blocks binding of its cognate ligand, stromal cell derived factor-1a (SDF-1a), also known 
as CXCL12. Plerixafor is used in this protocol as a CXCR4 antagonist.  
 
7.2.3. Description 
 
 
 
 
 
 
 
 
  
 
7.2.4. Packaging and Labeling Information 
 
 
 
 
 
7.2.5. Preparation 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
7.2.6. Calculation of Dose 
 
 
 
 
 
 
  
 


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39
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
– 
  
 
7.2.7. Storage 
 
 
 
 
 
 
 
7.2.8. Stability 
 
 
 
 
 
 
 
 
7.2.9. Route of Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.10. Subject Care Implications 
 
 
 
 
 
 
 
 
 


 
40
7.2.11. Returns or Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Sanofi, the amount dispensed to, and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
8. 
CORRELATIVE/SPECIAL STUDIES 
 
Research samples will be collected at the discretion of the PI based on availability of supplies and 
safety of patient and staff. Sample collection, processing, storage, and shipment instructions will 
be provided in the Laboratory Manual. 
 
8.1. 
Tumor Tissue Studies 
 
Blocks or slides (twenty five unstained slides) will be collected from archived tissue. These slides 
will also be used for the evaluation of additional immune and tumor markers. See the Laboratory 
Manual for additional details regarding tissue collection, processing, storage, and shipment.  
 
Tumor biopsies will be collected per Section 9. Fine needle aspiration samples do not contain 
sufficient tissue contextual information and will not be obtained. Additional biopsies may be 
obtained during the course of therapy or at progression.  
 
To explore the association of the tumor microenvironment and clinical responses, archived tumor 
tissue and tumor tissue obtained at baseline and during treatment will be compared. PD-L1 
expression may predict response to anti-PD-1 therapy [12]; however, PD-L1 is also upregulated 
in response to IFN- released by infiltrating T cells and could potentially be a predictor of response 
to any active immunotherapy. Pre- and post-treatment tumor biopsies will also be analyzed with 
immunohistochemistry and gene expression analysis for expression of T cell subset markers (CD3, 
CD4, CD8, FoxP3, Granzyme A/B, CD69), immune regulation (PD-L1, PD-L2, CTLA4, LAG-3, 
IDO1, TIM-3), and immune cell population markers (NK, DC, B cell, MDSC, M1/M2 
macrophages). 
 
To explore genetic determinants of response, whole-exome sequencing will be performed on DNA 
from tumors and matched normal tissue. We will characterize the tumor mutational landscape 
through exomic sequencing for mutation analysis and neoantigen prediction. 
 
TCR sequencing will be undertaken to evaluate the T cell repertoire through next-generation 
sequencing in the tumor tissue and to characterize peripheral immune responses. Gene expression 


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41
profiling will also be employed to identify gene signatures within the tumor microenvironment 
(TME) associated with response and survival. 
 
Results from the sequencing studies will not be released to the patients. These studies are for 
research purposes only, and the sequencing studies are not using a clinically validated platform. 
 
8.2. 
Whole Blood  
 
Whole blood will be collected to assess the baseline characteristic of the subjects enrolled and to 
correlate these molecular and clinicopathologic criteria with treatment response and toxicity.  DNA 
will be extracted from whole blood and used to evaluate for any germline mutations that may 
correlate with response or toxicity. 
 
Detailed instructions for sample collection, processing, storage, and shipment are provided in the 
laboratory manual. 
 
8.3. 
Peripheral Blood Mononuclear Cells (PBMCs) 
 
PBMCs will be collected per the study calendar. Post-treatment changes in PBMCs including 
effector, helper, and regulatory T cells, NK cells and macrophages through cell phenotyping 
analysis and gene expression profiling will be measured. Post-treatment expression of PD-1 and 
other lymphocyte activation markers will be measured and correlated with OS.  
 
T cells will be isolated and co-cultured with synthetic peptide neoantigens and will undergo TCR 
sequencing to assess for clonal expansion as previously described[13]. Gene expression will also 
be conducted on pre- and on-treatment PBMCs. 
 
Detailed instructions for sample collection, processing, storage, and shipment are provided in the 
laboratory manual. 
 
8.4. 
Serum and Plasma Marker Studies 
 
Sera and plasma will be collected per the study calendar to elucidate plerixafor exposure in this 
patient population, identify potential therapeutic targets, biomarkers, and predictors of response 
and autoimmune toxicity through proteomic approaches. DNA will be extracted from plasma 
samples and ctDNA levels commonly mutated genes may be assessed. 
 
Detailed instructions for sample collection, processing, storage, and shipment are provided in the 
laboratory manual. 
 
8.5. 
Serum and Salivary Cortisol  
 
Abnormalities in the diurnal variation of salivary cortisol in patients with advanced cancer have 
been associated with adverse prognosis[14, 15] and impaired immune cell function[16]. The most 
likely mechanism is a direct reduction in tumor infiltrating lymphocytes, in particular CD3 positive 
T cells (manuscript currently under review). 


 
42
 
Serum and salivary cortisol levels will be collected per the study calendar if available. Detailed 
instructions for sample collection, processing, storage, and shipment are provided in the 
laboratory manual. 
 
8.6. 
CT Scans for Body Composition 
 
Deidentified CT images will be sent to collaborators for evaluation of body composition for 
correlation with outcomes.  No additional imaging will be required. 
 
8.7. 
Diagnostic Tissue Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat or diagnoses 
immune related toxicities. Detailed instructions for sample collection, processing, storage, and 
shipment are provided in the laboratory manual.  
 
8.8. 
Genomic Analysis 
 
Genomic sequencing library construction, whole genome/exome sequencing, whole transcriptome 
sequencing, microbial sequencing, neoepitope prediction, mutation burden, and bioinformatic 
analysis will be performed either at an on-campus laboratory or at an off-campus sequencing 
service. All the samples will be de-identified before sending to any laboratory for sequencing.  The 
FASTQ files, BAM files and VCF files will be generated and analyzed. Genomic sequencing data 
will be stored and computations conducted using a JH IT managed subscription of Azure. 
 
Clinical analysis   
 
Several CLIA-certified laboratories now offer molecular profiling of cancer specimens in 
commercial and noncommercial settings and provide these results to patients and their physicians 
(e.g. Foundation Medicine, PGDx, Michigan Center for Translational Pathology, or JHU CLIA 
Laboratories). It is possible, therefore, that some of our research analyses will be conducted in 
these CLIA-certified environments.  If tissue or cells are evaluated with next generation 
sequencing strategies to provide a molecular profile of individual cancer specimens in a CLIA-
certified facility, these results will be made available to the patient and their physician.  Patient 
confidentiality will be maintained, and the patient’s identity will not be publicly linked to any 
study results.  Researchers may use the data set generated in the CLIA assay setting to study 
genetic alterations across a large number of genes important in cancer. Germline mutations are 
only identified in punitive cancer genes. Researchers will use the data set for exploratory research 
to study cancer cell heterogeneity. Some of the sequencing data obtained from the NGS strategies 
will be uploaded to government sponsored databases, such as GEO and dbGAP.  The results of the 
research studies may be published but subjects will not be identified in any publication. 
 
If a germline alteration of clinical importance (as judged by the Investigator) to the subject and his 
or her family members is identified by a CLIA-certified test in the course of this analysis, attempts 
will be made in writing to contact the subject and/or family members for genetic counseling 
referral. 
 


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43
9. 
STUDY CALENDAR 
Study Procedures 
Screen 
Cycle (21 days) 
EOT21 Safety 
FU22 
Clinical 
FU23 
Survival 
FU24 
D120 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D15 
Visit Windows (days)1 
-28 to D1 
± 3 
- 
- 
- 
- 
- 
- 
- 
+3/-2 
± 7 
+14 
± 14 
± 14 
Plerixafor2 
 
X 
 
 
 
 
 
Cemiplimab2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, Cancer, & Con Med Hx3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds, Adverse Events4 
 
X 
 
 
X 
 
 
 
X 
X25 
X 
X 
X 
 
Physical Exam, ECOG  PS4 
X 
X 
 
 
 
 
 
 
X25 
X25 
X 
 
X 
 
Vitals5 
X 
X 
 
 
X 
 
 
 
X 
X25 
X 
 
X 
 
Height6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
X25 
X25 
X 
 
X 
 
Hematology, Chemistry7,13 
X 
X 
 
 
X27 
 
 
 
X 
X 
X 
 
X 
 
Endocrine8,13 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
CD349 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
APTT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test12,13 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CA19-913 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
C-reactive protein (CRP)13 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Serum Cortisol, ACTH14, 26 
X 
 
 
 
 
 
 
X25 
 
 
 
 
 
Salivary Cortisol15, 26 
X 
 
 
 
 
 
 
X25 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI, RECIST/iRECIST16 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Whole Blood (up to 10cc)17, 26 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC (up to 120cc)18, 26 
 
X 
 
 
 
 
 
 
X25 
X25 
 
 
 
 
Plasma (up to 20cc) 18, 26 
 
X 
 
 
 
 
 
 
X25 
X25 
 
 
 
 
Serum (up to 5cc) 18, 26 
 
X 
 
 
 
 
 
 
X25 
X25 
 
 
 
 
Plerixafor PK (up to 12 cc)28 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
Tumor Biopsies19, 26 
X 
 
 
 
 
 
 
X25 
 
 
 
 
 
Archival Tissue26 
X 


 
44
Study Procedures 
Screen 
Cycle (21 days) 
EOT21 Safety 
FU22 
Clinical 
FU23 
Survival 
FU24 
D120 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D15 
Survival Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in person clinical trial visits 
or portions of clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the 
participants risks. Prior to initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit 
entails and confirm that the study participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will 
be obtained in accordance with the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the 
study visit will proceed as an in-person visit. Telemedicine visits will be conducted using HIPAA compliant method approved by the 
Health System and within licensing restrictions. 
 
1:   If necessary, a scheduled cycle may be delayed for up to 1 week. Longer delays to be approved by the Protocol Chair. 
2: Order of administration is Cemiplimab followed by Plerixafor. Subjects should be observed for a minimum of 30 minutes between 
each infusion. Plerixafor will be administered as a continuous 7-day IV infusion. Prepared plerixafor formulation is stable for 5 days 
at room temperature. Therefore, patients will return to clinic on day 4 to exchange the infusion bag and on day 8 to discontinue their 
plerixafor infusion.  
3:  Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of cancer, histology, histologic 
grade, date of initial diagnosis, date of metastatic diagnosis, prior cancer therapy regimens, MSI testing, and tumor mutation testing. 
If MSI testing has not been previously done, MSI testing may be done retrospectively if tissue is available. 
4: Complete physical examination and assessment of ECOG PS will be completed at baseline; focused physical examinations and 
assessment of ECOG PS will be conducted thereafter. Exams, concomitant medication, AE assessments, and ECOG PS can be 
evaluated up to 3 days prior to infusion on Day 1 of each cycle.  
5: Blood pressure, pulse, and temperature. On Day 1 of each cycle, vitals should be collected prior to both the Cemiplimab and 
Plerixafor administrations. On Cycle 1 Day 1, patients will have a 6 hour observation period with hourly vital sign assessment.  
6: Height will be obtained at or prior to baseline only.  
7:  Clinical hematology: CBC with differential ANC, ALC, AEC, and platelet count; serum chemistry: sodium, potassium, chloride, 
bicarbonate, glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, calcium, magnesium, 
and phosphorus. Calculated creatinine clearance (Cockcroft-Gault) is required at screening and on Day 1 of every cycle. 
8:   TSH (Total T3 and free T4 if TSH abnormal and clinically indicated). 
9: Day 1 and 4 of Cycle 1 and 2 only 
10: Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, and specific gravity. 
11: HIV antibody, hepatitis B surface antigen and hepatitis C antibody; additional virology may also be evaluated. Subjects who are 
hepatitis C antibody positive and confirmed negative viral load at screening will be allowed to enroll. 


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12: Pregnancy tests will be administered to WOCBP: serum pregnancy test is required at screening; serum or urine pregnancy tests are 
required before doses on Day 1 of each cycle.  
13: Labs may be collected within a window of up to 3 days prior to Day 1 of each cycle.  
14: ACTH collected at baseline only. Serum cortisol measured as scheduled with the exact record of time of sample acquisition (not 
time of sample processing) at baseline (any time prior to the first dose after eligibility is met), disconnection of plerixafor infusion 
(Cycle 1 Day 8) and Cycle 2 Day 1. Ideally this should be a fixed time, i.e. either 0800 or 1200. Collection will commence with 
saliva samples. 
15: Baseline saliva samples should be collected (if available) over 2 days (any time prior to the first dose after eligibility is met, D-7 to 
D-1), preferably when no other trial related procedures or visits are performed. On study saliva samples (if available) will be collected 
on Cycle 1 Day 7 and Cycle 1 Day 21 (i.e. one day prior to Cycle 2 Day 1 with a -1 day window for collection). The following five 
samples should be collected at each timepoint: 1. on awakening (right away, before breakfast), 2. 30 minutes after the first sample 
(still before breakfast), 3. 11:00am, 4. 4:00pm, and 5. just before bedtime (prior to brushing teeth). Collection of these samples will 
begin once kit and vendor are identified. 
16: Spiral CT of thorax, abdomen and pelvis (and other imaging studies as clinically indicated to evaluate suspected sites of metastatic 
disease). If a subject cannot have a CT scan (e.g., allergy to contrast dye), an MRI should be performed. On study radiologic 
evaluations and tumor measurements (RECIST/iRECIST per Appendix B and C) will be at baseline, every 9 weeks (+/- 2 week), 
and the EOT evaluation (± 4 weeks). The EOT scans do not need to be repeated if one has been done within the past 6 weeks. Weeks 
are in reference to calendar week and should not be adjusted due to dosing delays. 
17: Baseline only (any time prior to the first dose after eligibility is met) 
18: Whole blood for PBMC, plasma, and serum will be collected at baseline (any time prior to the first dose after eligibility is met), 
Cycle 1 Days 8 and 15, Cycle 2 Days 1 and 8, Cycle 4 Day 1, and Cycle 7 Day 1. Plasma and serum samples will also be collected 
on Day 8 of Cycles 4 and 7. Additional optional blood samples may be obtained later in the course of study treatment if patients 
have a response of interest. Detailed instructions for sample collection, processing, and shipment are provided in the Laboratory 
Manual.   
19: Tumor biopsies to be taken (4-6 cores per time point, if a subject’s tumor is thought to be reasonably safe and easy to biopsy) at the 
following timepoints: 1. Baseline (any time prior to the first dose after eligibility is met), 2. Prior to dosing on either Cycle 1 Day 8 
(-1 day) or Cycle 2 Day 1 (-3 day) for alternating patients, and 3. Optional biopsy may be obtained at the time of disease progression 
or if there is a response of interest. Fine needle aspiration will not be acceptable. Detailed instructions for tissue collection, 
processing, and shipment are provided in the Laboratory Manual.  
20: Cycle 1 Day 1 evaluations do not need to be repeated if they were conducted within 3 days of the pre-study evaluations.  
21: EOT visit will occur 30 (±7) days after the final dose (or within 7 days prior to initiation of a new anti-cancer treatment, whichever 
comes first). NOTE: CT scan assessment at EOT will occur 30 days (± 4 weeks) after the final dose. If the EOT visit occurs early, 
an assessment for AEs should be made by telephone or email on day 30 (±1) after last study dose. 


 
46
22: Subjects who discontinue treatment should be contacted by telephone or email at 100 days (+ 14 day reporting window) from their 
last dose of study drug or within 7 days before initiation of a new antineoplastic treatment (whichever comes first) to assess for 
treatment related toxicities. In addition, related SAEs occurring during this time should be reported as well. 
23: Subjects who discontinue treatment without disease progression will enter the clinical follow-up portion of the trial (Section 4.12.2). 
Clinical follow-up visits will occur every 12 weeks (± 2 weeks) until progression. After disease progression, subjects will enter the 
survival follow-up portion of the trial. 
24: Subjects who discontinue treatment and have disease progression will enter the survival follow-up portion of the trial (Section 
4.12.3). Subjects should be contacted every 12 weeks (± 2 weeks) to monitor overall survival. Information of other cancer therapies 
after discontinuation from the study treatment will be collected as well. 
25: Cycle 1 only. 
26: Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff. 
27: Cycle 1 and 2 only 
28: Whole blood for plerixafor plasma PK will be collected at baseline (any time prior to the first dose after eligibility is met), Cycle 1 
Days 4 prior to changing the infusion bag and Day 8 prior to stopping the infusion. Documentation of the infusion start/stop times 
along with the exact timing of the specimen is necessary to interpret the results. Detailed instructions for sample collection, 
processing, and shipment are provided in the Laboratory Manual. 
 


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10. 
STUDY ENDPOINTS 
 
10.1. Primary Endpoint 
 
The primary endpoint is ORR using iRECIST, which is defined as the proportion of subjects 
with PR or CR according to iRECIST. Subjects who discontinue due to toxicity or clinical 
progression prior to post-baseline tumor assessments will be considered as non-
responders.  Subjects who discontinue for reasons other than toxicity or clinical progression 
prior to the post-baseline tumor assessments or for other reasons prior to their first dose of 
study drug will be replaced and not included in the primary efficacy analysis. 
 
10.2. Secondary Endpoints 
 
The secondary endpoints are as follows: 
 
 ORR by RECIST v.1.1. 
 Safety assessed by the following measures: 
o Number of patients who have grade 3 or above drug-related toxicities 
o Frequency of drug-related toxicity by grade 
o Plerixafor- and cemiplimab-related infusion reactions 
o Immune-related AEs 
o Unacceptable toxicities 
o Vital signs: BP, pulse, respiratory rate, temperature 
o Physical examination 
o Changes in ECG readings  
o Clinical hematology: complete blood count (CBC) with differential ANC, ALC, AEC, 
and platelet count 
o Clinical serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, amylase, 
lipase, total protein, albumin, calcium, magnesium, and phosphorus 
o TSH, T3, Free T4 
 
10.3. Exploratory Endpoints 
 
The exploratory endpoints are as follows: 
 
 Overall survival (OS), progression free survival (PFS), time to-progression (TTP), disease 
control rate (DCR), best overall response (BOR), duration of response (DOR), duration of 
clinical benefit (DCB), and time to objective response (TTOR) measured by iRECIST and 
RECIST 1.1 (Appendix B).  
o Overall survival (OS) is defined as the number of months from the date of first 
treatment until death or end of follow-up (OS will be censored on the date the subject 
was last known to be alive for subjects without documentation of death at the time of 
analysis). 
o Progression-free survival (PFS) is defined as the number of months from the date of 
first treatment to disease progression (PD or relapse from CR as assessed using 


 
48
RECIST 1.1 criteria) or death due to any cause. PFS will be censored at the date of the 
last scan for subjects without documentation of disease progression at the time of 
analysis. iPFS is defined as the time to iUPD if the next scan (4-8 weeks later) confirms 
PD (state change from iUPD to iCPD, time to progression defined in this instance as 
iUPD). 
o Disease Control Rate (DCR) is defined as the percentage of subjects achieving stable 
disease or better (SD + PR + CR). 
o Best Overall Response (BOR) is defined in Appendix B. 
o Duration of Response (DOR) is defined as the number of months from the first 
documentation of a response to date of disease progression.  
o Duration of Clinical Benefit (DCB) is defined as the number of months from the date 
of first treatment to date of disease progression in those achieving a PR or CR. 
o Time to Objective Response (TTOR) is defined as the number of months from the date 
of first treatment to the date of documented partial or complete response. 
o Time to-progression (TTP) is defined as the number of months from the date of first 
treatment to the date of documented disease progression (PD or relapse from CR as 
assessed using RECIST 1.1 criteria). It differs from PFS in that it does not include death 
in the definition of an event.  TTP will be censored at the date of the last scan for 
subjects without documentation of disease progression at the time of analysis. 
 Immune subset analysis by IHC and gene expression profiling of the tumor  
 Sequencing of tumor 
 Immune subset analyses in PBMCs including effector, helper, and regulatory T cells, NK 
cells and macrophages 
 T cell receptor (TCR) repertoire analysis in PBMCs and tumors 
 Gene expression analysis 
 cfDNA analysis 
 Steady-state plerixafor concentrations to correlate with pharmacodyanmic endpoints (e.g., 
safety, response, and correlative studies). 
 
11. 
DATA REPORTING/ REGULATORY REQUIREMENTS 
 
AE guidelines and instructions for AE reporting can be found in Section 6 (Adverse Events: List 
and Reporting Requirements). 
 
Each Principal Investigator will comply with all regulated local reporting requirements and 
regulations, including ICH E6 guidelines for Good Clinical Practices. 
 
11.1. Data Collection and Processing 
 
All information will be collected on study-specific CRFs by study staff. These data will be 
reviewed for completeness and accuracy by the Principal Investigator.  
 
CRFs will be used to capture study results and data. The study coordinator or other authorized 
study personnel will transcribe data from source documents onto eCRFs. Before or between visits, 
the Protocol Chair, or designee may request copies of the CRFs for preliminary medical review. 


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Once the CRFs are complete and source-verified, the investigator must sign and date all required 
pages, verifying the accuracy of all data contained within the CRF.  
 
11.2. Safety Meetings 
 
Scheduled meetings will take place weekly (or as needed based on enrollment) and will include 
the protocol principal investigator, study coordinator(s), research nurse(s), sub-investigators (as 
appropriate), collaborators (as appropriate), and biostatisticians (as appropriate) involved with the 
conduct of the protocol. During these meetings, matters related to the following will be discussed: 
safety of protocol participants, validity and integrity of the data, enrollment rate relative to 
expectation, characteristics of participants, retention of participants, adherence to protocol 
(potential or real protocol violations), data completeness, and progress of data for objectives. 
 
11.3. Monitoring 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-affiliated 
sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019).  The SMC Subcommittee will 
determine the level of patient safety risk and level/frequency of monitoring. The PI shall internally 
monitor the progress of the trial, including review and confirmation of all safety/treatment-related 
outcomes, response assessments, safety reports and/or any related source documentation. The 
protocol will be monitored externally by the SKCCC CRO QA Office. Additional data and safety 
monitoring oversight will also be performed by the SKCCC Safety Monitoring Committee (SMC 
- as defined in the DSMP).  
 
11.4. Study Documentation 
 
11.4.1. Informed Consent and Authorization for use and Disclosure of Protected 
Health Information 
 
Written informed consent and authorization of use and disclosure of protected health 
information (PHI) must be obtained from each subject (or the subject’s legally authorized 
representative) before performing any study-specific screening/baseline period 
evaluations. The ICF and authorization for use and disclosure of PHI, which is prepared by 
the investigator or the site, must be reviewed and approved by the Protocol Chair (or 
designee), the study monitor (if applicable), and the site’s IRB before the initiation of the 
study.  
 
11.4.2. Investigator Study Files 
 
Documentation about the investigator and study staff, the IRB and the institution, is 
required before study site initiation. A list of required documents will be provided by the 
Protocol Chair designee to each participating investigator. Copies of these documents as 
well as supplemental information, such as the investigator’s obligations, IB, clinical study 
protocol and amendments, safety information, investigational agent information, biological 
samples 
and 
laboratory 
procedures, 
SRM, 
study 
logs, 
and 
Protocol 


 
50
Chair/investigator/study monitor correspondence will be kept on-site in study site-specific 
files. 
 
The Protocol Chair or designee will be responsible for maintaining original and backup of 
all CRF data. The investigator is responsible for maintaining backup of all electronic data 
systems used for primary documentation or source documentation. Backup of electronic 
data will be performed periodically as described in the site-specific SOPs. Backup records 
must be stored at a secure location on site and backup and recovery logs must be maintained 
to facilitate data recovery. If an electronic medical records system that is not supported by 
the Protocol Chair or designee (or is discontinued or decommissioned) is used, the 
investigator must maintain a system to retrieve these records or arrange for the transfer of 
these records to an alternate electronic format or to paper. 
 
Changes to any electronic records require an audit trail, in accordance with 21 CFR 
11.10(e), and should include who made the changes and when and why the changes were 
made. An audit trail is defined as a secure, computer-generated, time-stamped electronic 
record that will allow reconstruction of the course of events relating to the creation, 
modification and deletion of an electronic record. Audit trails must be created 
incrementally, in chronological order and in a manner that does not allow new audit trail 
information to overwrite existing data. Audit trails should be in a readable format and 
readily available at the study site and any other location where electronic study records are 
maintained. 
 
Audit trails are generated automatically for eCRFs. The investigator is responsible for 
maintaining audit trails of all electronic data systems used for primary documentation or 
source documentation. 
 
11.4.3. Case Report Forms and Source Documentation 
 
The investigator must make study data accessible to the site monitor, to other authorized 
representatives of the Protocol Chair (or designee) and to the appropriate regulatory 
authority inspectors. The original CRF for each subject will be checked against source 
documents at the study site by the site monitor. 
 
11.4.4. Retention of Study Documents 
 
According to ICH E6, all CRFs, as well as supporting paper and electronic documentation 
and administrative records, must be retained for at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing 
applications, or at least 2 years have elapsed since the formal discontinuation of clinical 
development of an individual product. Longer retention periods may apply. The Protocol 
Chair (or designee) will notify investigators as to when documents no longer need to be 
retained. No study documents will be destroyed or moved to a new location without prior 
written approval from the Protocol Chair (or designee). If the investigator relocates, retires 
or withdraws from the clinical study for any reason, all records required to be maintained 


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51
for the study should be transferred to an agreed-upon designee, such as another investigator 
at the institution where the study was conducted. 
 
Audit trails for electronic documents must be retained for a period at least as long as that 
required for the subject electronic records to which they pertain. The investigator must 
retain either the original or a certified copy of audit trails. 
 
11.4.5. Data Confidentiality and Subject Anonymity 
 
All information about the nature of the proposed investigation provided by the Protocol 
Chair or their representative to the investigator (with the exception of information required 
by law or regulations to be disclosed to the IRB, the subject or the appropriate regulatory 
authority) must be kept in confidence by the investigator. 
 
The anonymity of participating subjects must be maintained. Subjects will be identified by 
their initials and an assigned subject number on CRFs and other documents retrieved from 
the site or sent to the Protocol Chair, study monitor, Sanofi, regulatory agencies, or central 
laboratories/reviewers. Documents that identify the subject (e.g., the signed ICF) must be 
maintained in strict confidence by the investigator, except to the extent necessary to allow 
auditing by the appropriate regulatory authority, the study monitor, Protocol Chair or their 
representative. 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1. Study Design/Endpoints 
 
Sample Size 
 
This is an open-label, two stage, phase 2 study to evaluate the safety and clinical activity of 
plerixafor and cemiplimab in patients with metastatic pancreatic adenocarcinoma. The primary 
endpoint is objective response rate (ORR) assessed using iRECIST.   
 
The treatment regimen would be considered of insufficient activity for further study in this 
population if response rate (irORR) is 7.7% or less[1], and the minimum required level of efficacy 
that would warrant further study is an irORR of 20%.  The sample size is calculated to detect an 
improved irORR from 7.7% to 20%. A modified Simon’s two-stage design is planned. A total of 
21 patients will be entered in the first stage. If <=1 subject responds, the treatment will be 
terminated and we will conclude the regimen is ineffective. If >=2 subjects respond, then 
additional 18 patients will be enrolled.  If a total of 5 or fewer subjects respond in stage one and 
two combined, we consider the regimen ineffective. If a total of 6 or more respond, we conclude 
the regimen is promising and warrant further study. The maximum sample size will be 39. 
 
The design provides 80% power to detect the difference between the null hypothesis irORR of 
7.7%[1] to the alternative rate of 20% with one-sided type I error 0.07 (target type I error 0.1). The 
probability of early stopping at first stage is 0.51 if the true irORR is 7.7%.  
 


 
52
Statistical Analyses 
 
The primary endpoint is objective response, defined as complete response (CR) or partial response 
(PR) per iRECIST. Objective response rate (irORR) will be estimated as the proportion of subjects 
whose best overall response is either a CR or PR with corresponding 95% CI. The evaluable 
population for the analysis is all subjects who receive at least one dose of study drug, and have at 
least one post-baseline tumor assessments or discontinue due to toxicity or clinical progression 
prior to post-baseline tumor assessments.   
 
Exploratory endpoints include progression-free survival (PFS), overall survival (OS), and 
objective response per RECISIT 1.1, duration of response (DOR), disease control (DCR), time to 
progression (TTP). PFS is defined as the time from the first day of study treatment to the date of 
the first documented tumor progression or death due to any cause, whichever occurs first. Subjects 
who did not progress or die will be censored on the date of their last tumor assessment.  Overall 
survival (OS) is the time from the first day of study treatment to the date of death due to any cause. 
A subject who has not died will be censored at last known date alive. Kaplan-Meier curves will be 
used to summarize OS. Time to-progression (TTP) is defined as the number of months from the 
date of first treatment to the date of documented disease progression (PD or relapse from 
CR).Among patients with an objective response, DOR is defined as the time between the date of 
initial complete or partial response to the date of the first documented tumor progression or death 
due to any cause. Subjects who neither progress nor die will be censored on the date of their last 
tumor assessment. Summary statistics will be presented for DOR. Kaplan-Meier method will be 
used to summarize time-to-event outcomes PFS, OS, TTP and DOR. Rate of OR and DOR will be 
estimated along with 95% confidence intervals. The outcomes will be assessed using RECIST 1.1 
and also iRECIST unless otherwise defined. 
 
For biomarkers, potential relationships between biomarker data and efficacy or safety endpoints 
will be investigated aimed at identifying baseline biomarkers that may be used to prospectively 
identify subjects likely (or not likely) to respond to the treatment and to identify subjects who may 
be predisposed to having adverse reactions to treatment. Steady-state plerixafor concentrations 
will be correlative with response using appropriate non-parametric analysis. These exploratory 
biomarker analyses will be completed with biomarkers measured in blood and in tumor samples.  
 
12.2. Safety Analysis 
 
The safety analysis will be performed in all treated subjects. AE data will be listed individually 
and incidence of AEs summarized by system organ class and preferred terms within a system organ 
class for each cohort.  When calculating the incidence of AEs, each AE (based on preferred 
terminology defined by CTCAE version 5.0) will be counted only once for a given subject.  In 
analyses of grade and causality, if the same AE occurs on multiple occasions, the highest grade 
and strongest relationship to study drug will be assumed.  If 2 or more AEs are reported as a unit, 
the individual terms will be reported as separate experiences.   
 
Changes in vital signs, hematology and clinical chemistry parameters from baseline to the end of 
the study will be examined.  Toxicity will be tabulated by type and grade. Toxicities will be 


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53
characterized according to the CTCAE version 5.0.  Treatment-emergent changes from normal to 
abnormal values in key laboratory parameters will be identified. 
 
The study will include a safety run-in for the first six patients. If more than 1 of the first 6 patients 
experiences an unacceptable toxicity within the first cycle, then enrollment will be halted and the 
overall risk-benefit ratio of the study will be reconsidered. At any time thereafter, if more than 
33% of patients are observed to experience unacceptable toxicity within the first cycle, enrollment 
will be halted and the safety of the combination will be re-evaluated. Complete unacceptable 
toxicity criteria can be found in Section 4.7. The enrollment stops if: 
 
Number of 
Patients with 
AE > 33% 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
In number of 
patients 
between 
6 
7-9 
10-
12 
13-
15 
16-
18 
19-
21 
22-
24 
25-
27 
28-
30 
31-
33 
34-
36 
37-
39 
 
The operating characteristics of this stopping rule for toxicity, starting from the 6th patient, are 
shown below and based on 5000 simulations. 
 
Risk of AE 
0.10 
0.20 
0.25 
0.30 
0.33 
0.40 
0.45 
0.50 
0.55 
0.60 
% of time study stops 
12.4% 45.8% 
63% 
78.7% 
85% 
96.3% 
99% 
99.7% 
100% 
100% 
Expected sample size 
34.98 
24.64 
19.62 
15.25 
13.02 
9.04 
7.69 
6.81 
6.41 
6.19 
 
 
 
 
 
 


 
54
13. REFERENCES 
 
1. 
ONIVYDE™ Prescribing Information  
2. 
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 
66(1): p. 7-30. 
3. 
Torre, L.A., et al., Global cancer statistics, 2012. CA Cancer J Clin, 2015. 65(2): p. 87-108. 
4. 
Rahib, L., et al., Projecting cancer incidence and deaths to 2030: the unexpected burden 
of thyroid, liver, and pancreas cancers in the United States. Cancer Res, 2014. 74(11): p. 
2913-21. 
5. 
Burris, H.A., 3rd, et al., Improvements in survival and clinical benefit with gemcitabine as 
first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin 
Oncol, 1997. 15(6): p. 2403-13. 
6. 
Moore, M.J., et al., Erlotinib plus gemcitabine compared with gemcitabine alone in 
patients with advanced pancreatic cancer: a phase III trial of the National Cancer 
Institute of Canada Clinical Trials Group. J Clin Oncol, 2007. 25(15): p. 1960-6. 
7. 
Conroy, T., et al., FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N 
Engl J Med, 2011. 364(19): p. 1817-25. 
8. 
Von Hoff, D.D., et al., Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. N Engl J Med, 2013. 369(18): p. 1691-703. 
9. 
Wang-Gillam, A., et al., Nanoliposomal irinotecan with fluorouracil and folinic acid in 
metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a 
global, randomised, open-label, phase 3 trial. Lancet, 2016. 387(10018): p. 545-57. 
10. 
Biasci, D., et al., CXCR4 inhibition in human pancreatic and colorectal cancers induces an 
integrated immune response. Proc Natl Acad Sci U S A, 2020. 117(46): p. 28960-28970. 
11. 
Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20. 
12. 
Taube, J.M., et al., Association of PD-1, PD-1 ligands, and other features of the tumor 
immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res, 2014. 
20(19): p. 5064-74. 
13. 
Le, D.T., et al., Mismatch-repair deficiency predicts response of solid tumors to PD-1 
blockade. Science, 2017. 
14. 
Cohen, L., et al., Depressive symptoms and cortisol rhythmicity predict survival in 
patients with renal cell carcinoma: role of inflammatory signaling. PLoS One, 2012. 7(8): 
p. e42324. 
15. 
Sephton, S.E., et al., Diurnal cortisol rhythm as a predictor of lung cancer survival. Brain 
Behav Immun, 2013. 30 Suppl: p. S163-70. 
16. 
Sephton, S.E., et al., Diurnal cortisol rhythm as a predictor of breast cancer survival. J 
Natl Cancer Inst, 2000. 92(12): p. 994-1000. 
17. 
Seymour, L., et al., iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol, 2017. 18(3): p. e143-e152. 
 
 
 


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APPENDIX A: 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. 
 
 


 
56
APPENDIX B: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 
1.1 CRITERIA FOR EVALUATING RESPONSE IN SOLID TUMORS 
 
RECIST version 1.1 will be used in this study for assessment of tumor response.  While either CT 
or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.   
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 >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with 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 might or might not be 
considered measurable unless there is evidence of progression in the irradiated site. 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. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as 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 subject, these are preferred for selection as target lesions. 
 
Target lesions:  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. 
 


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Non-target lesions:  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.  
 
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. 
 
Progressive Disease (PD): 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.  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
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. 
 
Evaluation of Non-Target Lesions 
 
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). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a subject 
to be considered in complete clinical response. 
 
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). 
 
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 


 
58
recorded since the treatment started).  The subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Subjects with Measurable Disease (i.e., Target Disease) 
 
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 RECIST 1.1 manuscript for further details on what is evidence of 
a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Subjects 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. 
 
Reference 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. 
Verweij. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 
1.1).  Eur J Cancer. 2009 Jan;45(2):228-47. 
 
 
 


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APPENDIX C: DESCRIPTION OF THE IRECIST PROCESS FOR ASSESSMENT OF 
DISEASE PROGRESSION  
 
Assessment at Screening and Prior to RECIST 1.1 Progression 
 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
 
Assessment and Decision at RECIST 1.1 Progression 
 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide 
whether to continue a participant on study treatment until repeat imaging is obtained using the 
criteria outlined in Section 4.10.1. 
 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment. 
 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
 Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology. 
 Unequivocal progression of non-target lesion(s) identified at baseline 
 Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and 
iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, 
regardless of which factors caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as 
usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up to 5 
lesions total (up to 2 per organ), may be selected as New Lesions – Target.  The sum of diameters 
of these lesions will be calculated, and kept distinct from the sum of diameters for target lesions at 
baseline.  All other new lesions will be followed qualitatively as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 


 
60
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
 Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, 
compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared 
to a prior iUPD time point; this does not have to meet the “unequivocal” standard of 
RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time 
point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
 Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
 None of the progression-confirming factors identified above occurs AND 
 The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which 
iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The assessment 
of the subsequent confirmation scan proceeds in an identical manner, with possible outcomes of 
iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
 None of the progression-confirming factors identified above occurs, AND 
 The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), 
or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”.  This means that the next visit that shows radiographic progression, 


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61
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned.  
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated by 
any of the following events: 
 Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression.  The nadir 
is always the smallest sum of diameters seen during the entire trial, either before or 
after an instance of pseudo-progression. 
 Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this progression 
has not resolved, iUPD results from any significant further growth of non-target 
lesions, taken as a whole. 
 New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion 
sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  Progression 
must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except in one 
respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the 
burden of new lesions has increased from its smallest value (for new target lesions, their sum of 
diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will 
remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or 
until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication [17]. 
 
 
 
 
 


 
62
Table 2: Comparison between RECIST 1.1 and iRECIST 
 
 
RECIST 1.1 
iRECIST 
Definitions of disease: 
numbers, sites and 
target or non 
Measurable are diameters greater 
than 10 mm (15 for nodes 
maximum of 5 (2 per organ) 
No change from RECIST 1.1 
CR, PR or SD 
Cannot have met criteria for 
progression 
Can have had iUPD (more than 
once) but not iCPD before iCR, 
iPR or iSD 
Confirmation of CR or 
PR 
Only in non-randomized studies 
As per RECIST 1.1 
Confirmation of SD 
Not required 
As per RECIST 1.1 
New lesions 
Progression: recorded but not 
measured 
iUPD but only becomes iCPD if 
on the next scan there are new 
lesions or the size increases by 
greater than 5 mm 
Confirmation of 
progression 
Not required 
Required 
Consideration of 
clinical status 
Not required 
Clinical stability considered at 
iUPD to decide treatment 
continuation 
 
Table 3:    Trajectory of progression in iRECIST 
 
Target Lesions: iCR, Non-
target: iCR, no new lesions 
iCR 
iCR 
Target lesions: iCR, Non-
target: non iCR/non iUPD, no 
new lesions 
iPR 
iPR 
Target Lesions: iPR, Non-
target: non iCR/non iUPD, no 
new lesions 
iPR 
iPR 
Target lesions: iSD, Non-
target: non iCR/non iUPD, no 
new lesions 
iSD 
iSD 
Target lesions: iUPD with no 
change or with a decrease 
from the last time point, Non-
target: iUPD with no change 
or decrease from last time 
point, new lesions 
NA 
 
 
New lesions confirm iCPD if 
new lesions previously 
identified and increased in 
size (≥ 5 mm in sum of 
measures for new lesions or 
any increase for new lesion 
non-target) or increase in 
number. If no change is seen 
in new lesions assignment 
remains iUPD 


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63
Target lesions: iSD, iPR, 
iCR, non-target: iUPD, no 
new lesions 
iUPD 
Remains iUPD unless iCPD 
is confirmed by increase in 
the size of non-targets (does 
not need to meet RECIST 1.1 
criteria) 
Target lesions: iUPD, non-
target: non iCR/non iUPD, no 
new lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed on the basis of 
further increase ≥ 5 mm; 
otherwise stays as iUPD 
Target lesions: iUPD, non-
target: iUPD, no new lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed on previously 
identified targets iUPD ≥ 5 
mm or non-target iUPD 
Target lesions: iUPD, non-
targets: iUPD, new lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed by increase of ≥ 5 
mm previously identified 
target, or non-target or an 
increase in size or number of 
new lesions 
Target lesions non iUPD or 
progression, non-targets: non 
iUPD or progression, new 
lesions 
iUPD 
Remains iUPD unless iCPD 
confirmed by increase in size 
or number of new lesions 
previously identified. 
Target lesions, non-target lesions and new lesions are defined according to RECIST 1.1 criteria: if 
no pseudoprogression occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD are the 
same. * Previously identified in the assessment prior to this time point. ‘I’ indicates immune 
responses assigned using iRECIST 
 
 
 
 


 
64
APPENDIX D: SAE REPORTING FORM 
 
 


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65
Serious Adverse Event Reporting Form 
 
Please notify: Dr. Le within 24 hours 
 
Sanofi within 24 hours 
 
Regeneron within 24 hours 
 
 
 
Protocol Title: 
 
 
A Phase 2 Study of Plerixafor and Cemiplimab in Metastatic Pancreatic 
Cancer 
Protocol 
Number: 
SGZ- 2018-12345 
J19113 
Signature of PI: 
 
 
 
Principal Investigator: 
 
 
Date of 
Report: 
 
 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria (check all 
that apply): 
Death    
Life-threatening 
 Hospitalization or Elongation of 
Existing Hospitalization 
 Other Important Medical Event 
 Cancer 
 Overdose 
 Other:______________________ 
Hospital Admission 
Date: 
Date Event 
Discovered: 
Hospital Discharge 
Date:   
SAE ID: 
Section A: Subject Information 
Subject ID: 
Subject Gender: 
Male 
Female 
 
Subject Age: 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Event Grade: 
Cause of death (if 
applicable): 
Event Outcome: 
 Not Recovered 
 Recovering 
 Recovered 
 Recovered with 
sequelae 
 Death 
 Unknown 
Event Onset Date (or Date of Death): 
 
Event End Date: 
Section C: Study Drug Information 
 
Investigational Product: Plerixafor (80mcg/kg/hr, Days 1-7) and Cemiplimab (350mg, Day 1) IV 
every 21 days 
 
Indication: Metastatic pancreatic ductal adenocarcinoma 


 
66
Number of Total Cycles: 
 
Action taken with the study drug: 
 
None 
 Interrupted 
 Delayed  
 Discontinued  
Drug(s) discontinued: 
Date of First Dose: 
 
Date of Last Dose prior to 
Event: 
 
Relationship to: 
Plerixafor  
Cemiplimab 
Underlying Disease 
Unrelated 
 
 
 
Related 
 
 
 
Section D: Brief Description of the Event: 
 
Section E: Relevant Tests/Laboratory Data 
 
Section F: Relevant Medical History 
 
Section G: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section H: Comments 
 
Additional Documents: 
 Please specify 
 
 
 
 
 
 
 
 


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67
APPENDIX E: AESI REPORTING FORM 
 
 


 
68
Adverse Event of Special Interest Reporting Form 
 
Please notify: Dr. Le within 24 hours 
 
Sanofi within 24 hours 
 
Regeneron within 24 hours 
 
 
 
 
Protocol Title: 
 
 
A Phase 2 Study of Plerixafor and Cemiplimab in Metastatic Pancreatic 
Cancer 
Protocol 
Number: 
SGZ- 2018-12345 
J19113 
Signature of PI: 
 
 
 
Principal Investigator: 
 
 
Date of 
Report: 
 
 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Addendum to: 
 
Event Onset Date: 
 
AESI ID: 
Date Event 
Discovered: 
Event End Date: 
Section A: Subject Information 
Subject ID: 
Subject Gender: 
Male 
Female 
 
Subject Age: 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Event Grade: 
Event Outcome: 
 Not Recovered 
 Recovering 
 Recovered 
 Recovered with sequelae 
 Death 
 Unknown 
Section C: Study Drug Information 
 
Investigational Product: Plerixafor (80mcg/kg/hr, Days 1-7) and Cemiplimab (350mg, Day 1) IV 
every 21 days 
 
Indication: Metastatic pancreatic ductal adenocarcinoma 
 
 


J19113/ Version 7.0 / May 13, 2022 
69
Number of Total Cycles: 
 
Action taken with the study drug: 
 
None 
 Interrupted 
 Delayed  
 Discontinued  
Drug(s) discontinued: 
Date of First Dose: 
 
Date of Last Dose prior to 
Event: 
 
Relationship to: 
Plerixafor  
Cemiplimab 
Underlying Disease 
Unrelated 
 
 
 
Related 
 
 
 
Section D: Brief Description of the Event: 
 
Section E: Relevant Tests/Laboratory Data 
 
Section F: Relevant Medical History 
 
Section G: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section H: Comments 
 
Additional Documents: 
 Please specify