Clinical trial NCT03258008
Conditions: Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites Malignant Neoplasms of Lip Oral Cavity and Pharynx Oropharyngeal Cancer
Keywords: Malignant neoplasms of lip oral cavity and pharynx Malignant neoplasms of ill-defined secondary and unspecified sites Oropharyngeal Cancer Oropharyngeal squamous cell carcinoma OPSCC Human Papillomavirus - positive (HPV+) Utomilumab PF-05082566 Anti-CD137 ISA101b
Sponsor: M.D. Anderson Cancer Center
Start date: 2018-04-04; Completion date: 2021-11-05
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if utomilumab, when given with ISA101b, is able to shrink or slow the growth of tumors in patients with incurable HPV+ oropharyngeal squamous cell carcinoma.

This is an investigational study. Utomilumab and ISA101b are not FDA approved or commercially available. They are currently being used for research purposes only. The study doctor can explain how the study drugs are designed to work.

Up to 27 participants will be enrolled. All will take part at MD Anderson.

Detailed description:
Study Drug Administration:

There are 28 days in each study cycle.

You will receive utomilumab by vein every 4 weeks for up to 12 doses beginning on Cycle 1 Day 1. The drug will be given over about 1 hour each time you receive it.

You will receive ISA101b as an injection under the skin every 4 weeks for 3 doses. You will receive 2 injections each time. One may be in your arm and one in your leg.

Length of Study:

You may continue taking utomilumab for up to 1 year as long as your doctor thinks it is in your best interest. You will no longer be able to take the study drug(s) if intolerable side effects occur or if you are unable to follow study directions. You may not be able to take the study drug(s) if the disease gets worse, which is explained below.

Your participation on the study will be over after the follow-up visits.

Study Visits:

On Day 1 of Cycles 1-12:

* You will have a physical exam.
* Blood (about 1 tablespoon) will be collected for routine tests, thyroid function tests, and liver function tests.
* If you can become pregnant, blood (about ½ teaspoon) or urine will be collected for a pregnancy test.
* During Cycles 1, 2, 3, 4, 8, and 12, blood (up to 10 tablespoons) will be drawn for biomarker testing (including genetic biomarkers).

At the end of Cycle 2 and every 8 weeks after that, you will have an MRI or CT scan to check the status of the disease.

Study Continuation:

If the disease appears to have gotten worse, you may still be eligible to continue receiving your assigned study drug(s). This is because you may be benefitting from the study drug(s) even though the tumor(s) got larger. Your doctor will discuss this with you.

If this happens, your doctor will talk to you about whether or not you want to continue. If you do continue taking part in the study, you will follow the study visits as described above.

However, there are risks of continuing to receive the study drug(s) because the disease may actually be getting worse. You are still at risk for side effects due to utomilumab and ISA101b. Continuing on this study could also delay starting other treatments. The disease may get worse to the point that you are no longer able to receive other treatments. There are also risks from the additional tests that may be performed, such as biopsies and blood draws. You and your doctor will discuss these possible risks, and you will be asked to decide if you want to continue receiving the study drug(s).

End-of-Treatment and Follow-up Visits:

At about 30 days after your last study drug dose:

* You will have a physical exam.
* Blood (about 1 tablespoon) will be collected for routine tests, thyroid function tests, and liver function tests.
* If you are able to become pregnant, blood (about ½ teaspoon) or urine will be collected for a pregnancy test.

At about 70 days after your last study drug dose:

* You will have a physical exam.
* Blood (about 1 tablespoon) will be collected for routine tests, thyroid function tests, and liver function tests.
* If you are able to become pregnant, blood (about ½ teaspoon) or urine will be collected for a pregnancy test.

You will also be called every 3 months up to 1½ years and asked about your health. Each call should last about 10-15 minutes.

If you stopped taking the study drug for reasons other than the disease getting worse, you will continue to have MRI/CT scans every 8 weeks. If the disease appears to get worse, or you start a new anticancer therapy, these scans will stop.

Arms: arm 1: Utomilumab by vein every 4 weeks for up to 12 doses beginning on Cycle 1 Day 1.

ISA101b as an injection under the skin every 4 weeks for 3 doses. Participants receive 2 injections each time.
Interventions: intervention 1: Utomilumab intervention 2: ISA101b
Intervention descriptions: intervention 1: Utomilumab given by vein on Cycle 1 Day 1. Cycle 1-2 100 mg, Cycle 3-12 50 mg until progressive disease, toxicity, or 1 yr. intervention 2: ISA101b 100 mcg/peptide given subcutaneously every 4 weeks x 3 doses beginning cycle 1 day 1.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
2017-0145 
 
Phase II Trial of Utomilumab and ISA101b Vaccination in Patients with HPV-16-Positive 
Incurable Oropharynx Cancer  
 
Coordinating Center: 
University of Texas M.D. Anderson Cancer Center 
Chair: 
Bonnie Glisson, MD 
1515 Holcombe Blvd, Unit 0432 
Houston, TX 77030 
Telephone: 713-792-6363 
Fax: 713-792-1220 
bglisson@mdanderson.org 
 
 
 
 
 
 
 
Version Date: 3.20.2018 
 NCT03258008


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TABLE OF CONTENTS 
 
 
1.0 INTRODUCTION AND STUDY RATIONALE 
Pages 4 - 16 
1.1 STUDY RATIONALE 
1.1.1 Utomilumab 
1.1.2 ISA 101 
1.1.3 Combination of Utomilumab and ISA 101 
1.1.4 Dose and Schedule of Utomilumab 
1.1.5 Dose and Schedule of ISA 101 
1.2 RESEARCH HYPOTHESIS 
1.3 OBJECTIVES 
1.3.1 Primary Objective 
1.3.2 Secondary Objectives 
1.3.3 Exploratory Objectives 
1.4 MECHANISM OF ACTION 
1.4.1 Mechanism of Action of SLP-HPV-16 Vaccine 
1.4.2 Mechanism of Action of Utomilumab 
1.4.3 HPV Positive Malignancies 
1.4.4 HPV-16 SLP and ISA 101 Clinical Results 
1.4.5 Utomilumab  Clinical Results 
1.5 OVERALL RISK/BENEFIT ASSESSMENT 
2.0 INVESTIGATIONAL PLAN 
Pages 17 - 22 
2.1 Study Design and Duration 
2.2 Study Population 
2.2.1 Inclusion Criteria 
2.2.2 Exclusion Criteria 
2.2.3 Women of Childbearing Potential 
2.3 Concomitant Treatments 
2.3.1 Prohibited and/or Restricted Treatments 
2.3.2 Other Restrictions and Precautions 
2.3.3 Permitted Therapy 
2.4 Discontinuation of Subjects from Treatment 
3.0 TREATMENTS 
Pages 22 - 27 
3.1 Study Treatments 
3.2 Handling and Dispensing 
3.3 Selection and Timing of Dose for Each Subject 
3.3.1 Dose Delay Criteria 
3.3.2 Dose Reductions 
3.3.3 Criteria to Resume Dosing 
3.3.4 Treatment Beyond Disease Progression 
3.3.5  Treatment Discontinuation Criteria 
3.3.6 
Treatment of Infusion-Related Reactions 
3.3.7 Treatment of ISA101b Related System Reactions 
3.4 Destruction and Return of Study Drug 
 
 
 
 


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4.0 ASSESSMENT FOR SAFETY AND EFFICACY 
Pages 27 - 33 
4.1 Safety Assessments 
4.2 Efficacy Assessments 
4.3 Other Assessments 
5.0 SAFETY MONITORING AND REPORTING                                Pages 33 - 38 
5.1 ADVERSE EVENTS: Definitions and Reporting 
5.1.1 Serious Adverse Events Reporting 
5.1.2 Communication between Investigator and BMS and ISA 
5.2 Laboratory Test Abnormalities 
5.3 Pregnancy 
5.4 Overdose 
5.5 Potential Drug Induced Liver Injury (DILI) 
5.6 Other Safety Considerations 
6.0 STATISTICAL CONSIDERATIONS                                             Pages 39 - 42 
6.1 Sample Size Determination 
6.2 Dose-Limiting Toxicity 
6.3 Stopping Rules for Toxicity 
6.4 Populations for Analyses 
6.5 Endpoint Definitions 
6.5.1 Primary Endpoint 
6.5.2 Secondary Endpoints 
6.5.3 Exploratory Endpoints 
6.5.4 Safety Analyses 
7.0 References                                                                                   Pages 42 - 45 
 
Appendix 1 RECIST 1.1 criteria                                                    Pages 45 - 51  
Appendix 2 Immune-Related Response Criteria (irRC)          Pages 52 - 54  
Appendix 3 Immune-Related Adverse Event Management           Pages 55 - 58 


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1.0. Introduction 
Infection with Human Papillomavirus (HPV) causes substantial cancer burden including 
nearly all cervical, majority of oropharyngeal, and a significant percentage of anal, penile, 
vulvar, and vaginal cancers. The HPV vaccines currently available are only preventive, must 
be given before sexual debut/HPV exposure, and have little market penetration. Additionally, 
the latent period between exposure and diagnosis of cancer is decades-long; therefore, even 
if vaccine use is increased in the near term, high risk HPV-related cancers will continue to 
increase and persist for decades to come. 
 
Recent work has identified signaling pathways between tumor and immune cells which act to 
suppress immune rejection. Inhibition of signaling with antibodies to key proteins, cytotoxic T 
lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), has resulted in 
very promising tumor shrinkage and prolonged survival in patients with a variety of cancers, 
including lung cancer, a tumor long-considered non-immunogenic. Specifically in platin- 
refractory squamous cancer of the head and neck (SCCHN), including HPV+ oropharyngeal 
squamous carcinomas (OPSCC), inhibition of PD-1 with nivolumab is associated with superior 
progression-free and overall survival (PFS, OS) rates compared to standard non- platin 
cytotoxins and cetuximab (1). However, only 16% (95% Cl:11-22) of patients with HPV+ 
OPSCC respond, with a median OS of 9 months.  Very similar response and survival rates 
have been reported with pembrolizumab in similar patients (2). These data emphasize the 
importance of addressing mechanisms of resistance to immune response. Preliminary results 
from our rial of nivolumab and an HPV-16 synthetic long peptide vaccine (ISA101) 
(NCT02426892) support that concept, based on a response rate that is more than doubled 
relative to nivolumab alone in patients with HPV+ oropharynx cancer (3). This observation 
underlines the potential to target non-self, HPV- specific antigens with vaccination and 
potentially synergize with immune checkpoint therapies 
 
In the trial described herein, a T cell co-stimulatory agonist monoclonal antibody targeting 
CD137 (4-1BB), utomilumab will be combined with ISA101b, further exploring the hypothesis 
that immune therapy for HPV-related cancers should directly engage the immune response 
to viral antigens to maximize efficacy.  
 
1.1   Rationale 
 
1.1.1   Utomilumab (PF-05082566): Utomilumab is an investigational intravenous (IV) fully 
human IgG2 monoclonal antibody that binds to the extracellular domain of human 4-1BB with 
high affinity and specificity and is capable of 4-1BB agonism. 4-1BB (CD137), first identified 
as an inducible costimulatory receptor expressed on activated T cells, is a membrane 
spanning glycoprotein of the Tumor Necrosis Factor (TNF) receptor superfamily. Current 
understanding of 4-1BB indicates that expression is generally activation dependent and 
encompasses a broad subset of immune cells. 4-1BB is undetectable on the surface of naive 
T cells but expression increases upon activation. Upon 4-1BB activation, pro-survival 
members of the TNFR-associated factor (TRAF 1 and 2) are recruited to the 4-1BB 
cytoplasmic tail resulting in downstream activation of NFkB and the Mitogen Activated Protein 
(MAP) Kinase cascade including Erk, Jnk, and p38 MAP kinases. NFkB activation leads to 
upregulation of Bfl-1 and Bcl-XL, pro-survival members of the Bcl-2 family. The pro-apoptotic 
protein Bim is downregulated in a TRAF1 and Erk dependent manner (4). 
 
Numerous studies of murine and human T cells indicate that 4-1BB promotes enhanced 
cellular proliferation, survival, and cytokine production (5). Reports have shown that 4-1BB 
agonist mAbs increase costimulatory molecule expression and markedly enhance cytolytic T 


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lymphocyte responses, resulting in anti-tumor efficacy in various models. 4-1BB agonist mAbs 
have demonstrated efficacy in prophylactic and therapeutic settings and both monotherapy 
and combination therapy tumor models and have established durable anti-tumor protective T 
cell memory responses (6). 4-1BB agonists also inhibit autoimmune reactions in a variety of 
autoimmunity models (7). This dual activity of 4-1BB offers the potential to provide anti-tumor 
activity while dampening autoimmune side effects that can be associated with immunotherapy 
approaches that break immune tolerance (8-9). 
 
1.1.2  ISA101: ISA101 is a therapeutic HPV-16 vaccine consisting of 9 overlapping long E6 
peptides (25-mer to 32-mer E6 peptides) and 4 overlapping long E7 peptides (35-mer E7 
peptides) (SLP-HPV-16 vaccine). These peptides overlap by 10 to 18 residues and cover the 
complete sequence of HPV16 E6 and E7 oncoproteins. These long peptides have the 
capacity to effectively deliver antigens to dendritic cells (DC). Proper DC activation by adjuvant 
then induces CD4+ and CD8+ T-cell responses by MHC class I and MHC class II presentation 
of the HPV16 E6/E7 processed epitope peptides and provision of secondary co-stimulatory 
signals. Properly activated CD4 T cells increase surface CD40-ligand (CD40L) expression, 
causing DC activation through CD40L-CD40 triggering. This in turn leads to CD8 T cell 
activation associated with expansion of CD8+ cytotoxic T cells capable to reach and kill tumor 
cells that express E6 and E7 epitopes. 
 
In patients with high-grade premalignant vulvar lesions (VIN) the prototype HPV‐16‐ SLP 
vaccine produced regression of lesions in 15/19 patients at 12 months of follow up and 9/19 
had complete disappearance of disease that was durable in all 9 at 24 months (10). 
Importantly, complete clinical responses were correlated with stronger interferon- gamma- 
associated T cell responses and all complete responders developed HPV-16 specific 
immunity. Subsequently a pilot study in 12 patients with advanced cervical cancer indicated 
that T-cell responses are enhanced when combining appropriately timed chemotherapy 
(carboplatin/paclitaxel) and the HPV-16 vaccine (10, 11). The mechanisms of enhanced 
immune response upon delivery of a single vaccine dose 2 weeks after the last dose in the 
second cycle of carboplatin/taxol chemotherapy appeared to be depletion of myeloid derived 
suppressor cells without depletion of T cell function or numbers. An additional Phase 2 trial in 
patients with advanced cervical cancer, CervISA, is being conducted to evaluate the optimal 
dose of ISA101, with or without interferon alpha, that produces a robust immune response. 
 
In the trial proposed herein, a second formulation of the vaccine (ISA101b) will be used. 
ISA101b is missing one E7 peptide, leaving a gap in coverage of only 7 amino acids. The 
new vaccine is under evaluation for both safety and immunogenicity in the CervISA trial, with 
qualitative comparison to ISA101 planned (ISA101-ISA101b Investigator’s Brochure v10a). 
However, the small gap in coverage is not predicted to affect immunogenicity substantively. 
 
1.1.3 Combination of Utomilumab and ISA 101: The immunologically foreign nature of the 
HPV E6 and E7 proteins, coupled with their critical role in maintaining the oncogenic state, 
makes them ideal target antigens for therapeutic cancer vaccination. While peptide-, protein-, 
viral- and DNA-based vaccines targeting E6 and E7 have been studied both pre-clinically and 
in clinical trials, most fail to induce regression of established HPV+ tumors (12). While a 
number of these vaccines extend survival, few can induce regression of established cancer, 
suggesting that the T cells they elicit lack the capacity to overcome the suppressive tumor 
microenvironment and eradicate bulky disease (13). Of the HPV E6/E7 vaccines in clinical 
trials, ISA101 has demonstrated noteworthy efficacy inducing regression of high-grade VIN 
lesions and meriting evaluation in combination studies with cytokine therapy, chemotherapy, 
and immune checkpoint blockade for the treatment of metastatic HPV+ cancers. 


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Within the tumor microenvironment, tumor and stromal cells engage co-inhibitory receptors 
on T cells to attenuate potentially tumoricidal immunity (14). We have previously shown that 
combination blockade of two of these T cell checkpoint  receptors,  CTLA-4 and PD-1, 
promotes synergistic tumor rejection of murine melanoma (15). Activation of T cell co- 
stimulatory receptors using agonist antibodies, alone or in combination with checkpoint 
blockade, can also extend T cell survival and effector function with the microenvironment and 
promote tumor rejection (16). Among co-stimulatory receptors, we have found that the tumor 
necrosis factor receptor superfamily member 4-1BB, the target of utomilumab, has a unique 
capacity to activate both T cells and antigen presenting cells (APC), which fosters generation 
of an exquisitely cytotoxic T cell phenotype termed ThEO/TcEO (17). 
 
Recently, we demonstrated a unique potential of 4-1BB agonist antibodies to potentiate the 
therapeutic effects of an HPV E6/E7 vaccine against both sub-cutaneous and vaginally 
implanted HPV+ tumors in a murine syngeneic pre-clinical model (18). Neither provision of 
OX-40 or CD40 agonist antibodies, nor blockade of the checkpoint receptors CTLA-4 or PD- 
1 could replicate the therapeutic efficacy of 4-1BB agonist antibodies in this setting. As the 
HPV vaccine used in these studies is not available clinically, we have also confirmed that 4- 
1BB agonist antibodies enhance the therapeutic efficacy of the ISA101 vaccine when used in 
the same syngeneic HPV+ tumor model (Figure 1). The goal of the proposed study is to 
augment the E6/E7-specific T cells generated by therapeutic HPV vaccination with ISA101 
so that they can expand in magnitude, infiltrate sites of HPV+ tumor, and maintain effector 
function in the suppressive microenvironment. 
 
With the above mentioned background, 
we propose this study in patients with 
incurable HPV-16+ cancers. Initially we 
will confine eligibility to patients with HPV 
+ OPSCC  who are platin refractory 
(progression on or within 6 months of 
platin treatment) during definitive or 
palliative treatment and naïve to PD-1 
inhibitors. 
This 
homogeneity 
will  
minimize variables that could confound 
interpretation of efficacy 
or immune monitoring in blood and tumor. 
Should the primary endpoint ( ORR ≥ 
6/25) be achieved in patients with platin-
refractory OPSCC, additional cohorts of 
patients with HPV-16+ anogenital primary 
cancers will be considered.  
 
1.1.4 Dose and Schedule of Utomilumab 
An ongoing phase 1 trial of utomilumab, alone in patients with mixed solid tumors, or in 
combination with rituximab for patients with CD20+ non-Hodgkin’s lymphoma, has accrued 
86 solid tumor patients and 47 patients with lymphoma as of June 2016. (NCT01307267). 
Dose levels from 0.006 mg/kg to 10 mg/kg i.v. every 4 weeks have been studied and generally 
well tolerated. For toxicity summary see 1.4.4.  Efficacy signals in both the solid tumor and 
lymphoma cohorts of the above trial have been limited to the lower dose levels (0.3 - 2.4 
mg/kg). Specifically with utomilumab mono-therapy, two patients with Merkel cell carcinoma 
attained CR and PR at 0.24 and 0.6 mg/kg, respectively and one patient with melanoma 
attained PR. Notably, only one patient with head and neck cancer has been treated. 
Pharmacokinetic data from 68 patients receiving doses from 0.006 to 5 mg/kg showed that 
only 7% of inter-patient variability was related to body weight. In addition, simulations 
indicated that exposure was similar between body weight- based and fixed dosing regimens. 
Thus, fixed dosing of utomilumab will be used in this trial. We will investigate a dose of 100 


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mg given i.v. every 4 weeks, corresponding roughly to 1.5 mg/kg.  At cycle 3 the dose will be 
reduced to 50 mg to hopefully avoid up-regulation of PD-1 expression  and increase in soluble 
4-1BB  that may be induced at prolonged dosing at 100 mg .  Both 50 and 100 mg doses of 
utomilumab are being studied in combination with avelumab and an OX-40 agonist mab 
(NCT02554812).  Utomilumab dosing starts on Cycle 1 Day 1. 
 
1.1.5 Dose and Schedule of ISA 101 
In completed and ongoing clinical studies with HPV-16-SLP, the precursor vaccine to ISA101, 
over 180 patients with HPV-induced pre-malignancy of the cervix and vulva have been 
administered the vaccine at least once at doses ranging from 20 to 300 μg per peptide 
[ISA101-101b Investigators Brochure, June 2016 (20) (21). Previous clinical trials utilizing 
HPV-16-SLP formulated with Montanide as monotherapy have demonstrated an acceptable 
safety profile for patients with malignancy, induction of robust T cell immune responses 
compared to pre-vaccination values, and clinical efficacy in patients with high grade VIN (10) 
(22). In patients with cervical dysplasia and advanced cervical cancer, it has been possible 
to show induction of specific T cell responses utilizing the HPV-16-SLP monotherapy 
approach (11, 23), but these remained below the level associated with clinical responses in 
the VIN trial, and therefore, as expected without convincing clinical impact. This indicates the 
need for improvement by co-treatment in patients with late stage HPV16-positive cancer. 
 
A phase I/II clinical trial, exploring the aforementioned chemo-immunotherapy co-treatment, 
called CervISA (NCT02128126), sponsored by ISA, is currently ongoing in Europe. This trial 
is investigating the safety and tolerability of different dose levels of ISA101 with or without 
pegylated interferon-alpha (IFNα) in combination with carboplatin and paclitaxel in patients 
with recurrent/metastatic incurable cervical cancer. Dose determination for the current trial 
has been chosen on the basis of CervISA and other trials that have shown 100 mcg per 
peptide given s.c. every 3 weeks x 3 doses to be safe and to elicit appropriate anti- HPV-16 
immune response (10, 22). The vaccine is delivered in two 0.5 ml injections, containing the 
E6 and E7 peptides, respectively. ISA 101b dosing starts on Cycle 1 Day 1. As indicated 
above, evaluation of the immunogenicity of the newly formulated vaccine ISA101b will be 
included in the CervISA trial. 
 
1.2 Research Hypothesis 
In patients with incurable HPV-16 + OPSCC, the combination of ISA101b and the 4-1BB 
(CD137) agonistic antibody, utomilumab, will produce HPV-specific immune response and 
increased clinical efficacy, in comparison to historical data with standard  anti-PD-1 therapy 
(nivolumab), with an acceptable safety profile. 
 
1.3 Objectives 
 
1.3.1 Primary Objective 
 
To determine the antitumor activity, as reflected in overall response rate (ORR), of 
utomilumab  combined with ISA 101 in patients with incurable HPV+ OPSCC. 


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1.3.2 Secondary Objectives 
 
To evaluate safety and tolerability of utomilumab  combined with ISA101 in patients 
with incurable HPV+ oropharyngeal squamous cell carcinoma (OPSCC). 
 
 
To evaluate immune-related ORR, duration of response,  progression-free and overall 
survival (PFS, OS), and  immune-related PFS 
 
 
To assess the value of peripheral and intra-tumoral ThEO/TcEO phenotype T cell 
formation as a pharmacologic and/or response predictive biomarker for utomilumab 
and  ISA101b. 
 
 
To assess the value of peripheral and intra-tumoral HPV E7 specific CD8 T cell 
frequencies as a pharmacologic and/or response predictive biomarker for utomilumab 
and  ISA101b. 
 
1.3.3 Exploratory Objectives: 
 
To explore other potential predictive biomarkers of response in tumor specimens and 
peripheral blood 
 
1.4 Mechanism of Action 
 
1.4.1 Mechanism of action of SLP- HPV- 16 Vaccine 
The proposed mode of action in relation to therapy of HPV-associated malignancies, is based 
on the fact that SLP of 25-35 amino acids in length require an obligatory processing step by 
DC in order for the resulting short peptides to bind to MHC class I and II molecules and become 
transported to the cell surface. DC can very efficiently process and present long peptides 
following direct cytoplasmic uptake and only DC can do this efficiently. Short exact MHC class 
I-binding peptides, in contrast, bind exogenously to MHC class I molecules of all nucleated 
cells that express surface MHC class I. Since most of these cells are not professional antigen- 
presenting cells such as DC, this leads to suboptimal antigen processing and presentation in 
the absence of co-stimulatory molecules. In addition the use of exact MHC class I-binding 
peptides does not stimulate CD4+ T cell immunity, which is  a prerequisite for optimal 
expansion of CD8+ killer cells and for CD8+ T cell memory. 
 
Pharmacokinetic parameters for ISA101 were not determined in the pre-clinical studies. 
Studies with other SLP vaccines, however, indicate that the distribution of the peptides is 
mainly restricted to the draining lymph nodes (20) (24). Furthermore, the investigational 
product is not metabolized in the conventional sense: the peptides are taken up by antigen 
presenting cells, which process the peptides into smaller entities, called T-cell epitopes, which 
are presented on the surface of the antigen presenting cell (APC). In the meantime, the APC 
traffics to a draining lymph node, where naive T cells recognize the T-cell epitopes and are 
activated by these epitopes. The peptides are degraded within APCs through normal 
degradation pathways. 
 
1.4.2 Mechanism of action of utomilumab 
In pre-clinical studies, utomilumab has exhibited the ability to increase lymphocyte 
proliferation. In small animal models developed to test the in vivo function, utomilumab was 
able to enhance expansion of human leukocytes in a dose dependent manner as evidenced 
by an increase in the proportion of human CD45+ cells in the peripheral blood of engrafted 


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mice. Similarly, a dose dependent increase in the proportion of human leukocytes expressing 
the proliferation marker Ki-67 was noted. In addition, utomilumab treatment of cynomolgus 
monkeys in single or multiple dose studies increased proliferation among cytotoxic central 
memory T-cells (CD8 TCM) in peripheral blood mononuclear cell (PBMC) samples. Taken 
together, these data demonstrate evidence of utomilumab’s ability to enhance lymphocyte 
response in vivo. 
 
Single-agent utomilumab has demonstrated the ability to promote anti-tumor immune activity 
in pre-clinical studies. Human tumor cell lines representing melanoma, colon, and prostate 
tumor types were tested in a xenogenic transplant model. Utomilumab does not bind to 
murine 4-1BB; therefore, primary human peripheral blood mononuclear cells (PBMC) from a 
healthy volunteer donor were mixed with tumor cells to set up the animal model. Once tumors 
were established, animals were treated with Utomilumab with efficacy against all 3 tumor 
types. 
 
1.4.3 HPV Positive Malignancies 
The causal role of HPV infections in the development of preneoplastic lesions and subsequent 
carcinoma has been unambiguously established (25) (26). Genital infections with high-risk 
HPV are mainly acquired through sexual activity (27-29) and are highly prevalent in young 
sexually active individuals. In the majority of infected subjects the infection is cleared within 
one year (30, 31). However, infection with the high-risk HPV type 16 (HPV16) is associated 
with a greater risk for progression and is most common in patients with HPV-related cancer 
(25, 32). HPV-16 encodes the two tumor-specific oncoproteins E6 and E7 that can elicit a 
favorable immune response in which specific T-cells play a critical role in the control and 
elimination of the HPV infection. The virus- specific interferon-γ (IFNγ)-producing CD4+ cells 
(Th1 cells) and CD8+ cytotoxic T- lymphocytes (CTL) are able to recognize  peptides 
processed from the oncoproteins E6 and E7 and contribute to the virus elimination (33, 34). 
 
However, in case of an uncontrolled persistent infection with a high-risk HPV type, the 
expression of the viral oncoproteins E6 and E7 contributes to the development of 
(pre)malignancies. Apparently, the spontaneous HPV-specific T-cell response fails in these 
patients and there is no or a negligible activation and expansion of the proper HPV16-specific 
CD4+ and CD8+ T cells (33, 34) 
 
Persistent HPV infection causes a variety of solid cancers including oropharyngeal, cervical, 
vulvar, vaginal, anal and penile cancers. HPV-related cancers are cured in the majority of 
cases when discovered at early stages with multimodality therapy including surgery, radiation 
therapy and chemotherapy. However, distant metastases may arise after longer intervals and 
in unusual sites (35, 36). Locoregional and distant recurrence are both problematic in 
advanced stage patients. Some patients with locoregional recurrence can be salvaged with 
multi-modal therapy. 
 
Standard treatment of incurable advanced disease, specifically in the case of HPV+ OPSCC 
consists of platinum- based doublet systemic chemotherapy +/- cetuximab, and yields median 
OS rates of ~ 1 year for both incurable locoregional and metastatic recurrence (37). Very 
recent data with the PD-1 inhibitors, nivolumab and pembrolizumab, in platin-refractory 
squamous cancer of head and neck (SCCHN), including HPV + OPSCC, demonstrates ORR 
of 16% and median OS of  8-9 months (1, 2). An FDA indication has been granted for 
pembrolizumab and nivolumab in HNSCC patients previously treated with platin-containing 
chemotherapy. These data do represent a substantive advance, but also underline the fact 
that a significant percentage of patients do not substantially benefit from PD-1 inhibition. 


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Clearly novel immunotherapy approaches merit evaluation in HPV+ OPSCC and other HPV- 
related cancers. 
 
1.4.4  HPV-16 SLP and ISA101 Clinical Results 
 
 
1.4.4.1 Clinical pharmacology summary 
Early studies were performed with a similar prototype vaccine manufactured at the Leiden 
University Medical Center (LUMC), identified as HPV-16-SLP. ISA101 is manufactured by a 
contract manufacturing organization for current trials sponsored or supported by ISA 
Therapeutics. Data developed with HPV-16-SLP may provide important information to help 
guide the development of ISA101 with respect to mechanism of action, the safety profile and 
biologic activity. Data from studies performed with the prototype vaccine, HPV-16-SLP, as 
distinct from ISA101, are specifically identified within this document. 
 
Clinical experience with HPV-16-SLP, the prototype of ISA101, has been obtained from 
several investigator-sponsored studies and available data have been provided to ISA. Initial 
clinical trials of HPV-16-SLP were mainly designed to assess the safety, tolerability and 
immunogenicity. ISA’s access to the safety data in these trials data is limited, and the data 
may not be complete as these studies have not been conducted, monitored or audited by ISA. 
ISA engaged an independent reviewer, Dr. M. van Poelgeest, in late 2011 to assess clinical 
safety data from studies conducted through November 18, 2011. This safety analysis focused 
on the two most common and important allergic reactions to ISA101: local injection site and 
systemic allergic reactions. This analysis provides the primary basis for understanding of the 
safety profile of HPV-16-SLP and hence, ISA101. More recent data on HPV-16-SLP have 
also been incorporated, as well as all available non-clinical and clinical data on ISA 101 
through May 31, 2014. 
 
Preclinical efficacy studies showed significant activity of the papilloma virus long peptide 
approach. In a preclinical model of HPV16-induced cervical cancer, vaccination with a single 
synthetic long peptide of HPV-16 E7 induced a strong HPV-16 specific immune response in 
inbred B6 mice, increased survival and mediated eradication of existing tumours. A second 
preclinical disease model in outbred rabbits used a set of long overlapping peptides of the 
entire sequence of cottontail rabbit papilloma virus E6 and E7, mimicking persistent HPV 
infections and related papilloma induced lesions. In this model, the long peptide vaccination 
approach resulted in similar effects: a strong induction of a  papilloma-specific immune 
response, clearing of viral DNA and control of papilloma induced wart growth. 
 
Pharmacokinetic parameters of ISA101 were not assessed in the preclinical studies. Studies 
with other synthetic long peptides, however, indicate that the distribution of the peptides is 
mainly restricted to DC in the draining lymph nodes (24). 
 
1.4.4.2 Safety summary 
Toxicology studies in rats (HPV-16-SLP) and rabbits (ISA101) showed that the vaccine 
induced high antibody levels against the immunogen and was well tolerated systemically after 
subcutaneous (s.c.) administration at high doses. In these studies, the vaccine was given 
together with an adjuvant, Montanide ISA 51 VG, hereafter referred to simply as Montanide, 
to mimic clinical studies. Doses in the rat were up to 120 μg per peptide per injection, while in 
the rabbit study the animal dose (300 μg per peptide per injection) was the same absolute 
dose as used in clinical trials, i.e. not adjusted for body weight or surface area. 
 
Local inflammation at the injection site was volume dependent which suggests that the 
formulation was at least partially responsible for this effect. The irritation persisted throughout 
the studies; recovery started when treatment stopped but was not completely resolved within  


2017-0145 
March 20, 2018 
 
11 
 
 
the 14-day recovery period. Systemic effects included transient, minor decreases in albumin 
content and albumin to globulin (A/G) ratios in the blood, increased spleen weight, and 
microscopic minor inflammatory changes in lungs, spleen and lymph nodes. These effects are 
considered indicative of an immune and/or inflammatory response. The immune responses 
are primarily local in nature and occur in microenvironments of the draining lymph nodes. 
 
Clinical experience with ISA101, per se, is limited as clinical studies were initiated in June 
2013. Two trials with ISA101 are enrolling patients as of the date of writing this protocol, 
 
CervISA: An open label phase I/II study in patients with advanced or metastatic 
(stage IVb) or recurrent HPV-16 positive cervical cancer for whom no curative treatment 
options exist. 
VACCAIN1: A study of ISA101 administered by intradermal injection without 
Montanide in patients with Anal Intraepithelial Neoplasia (AIN). 
In supporting clinical studies with HPV-16-SLP-Montanide approximately 180 patients with 
HPV-induced pre-malignant lesions and malignancies of the cervix and vulva have been 
administered the vaccine at least once at doses ranging from 50 to 300 μg per peptide. Of 
these patients, approximately 18 (~10%) have terminated vaccination due to local and/or 
systemic adverse events. 
 
The most important adverse events associated with HPV-16-SLP systemic effects include 
fever, chills, nausea, malaise and fatigue. Local reactions at the vaccination site include pain, 
redness swelling and itching. Adverse effects of HPV-16-SLP appear to be reported at a 
greater frequency and severity in patients with premalignant disease compared to patients with 
advanced cervix carcinoma. Generally the adverse events after HPV-16-SLP vaccination do 
not exceed grade 2 according to the CTC criteria. However, a number of more serious adverse 
events (CTC criteria grade 3), have been reported, including systemic allergic reactions and 
more serious local reactions such as ulcerations or fistulas at the vaccination sites that have 
led to withdrawal from study treatment in approximately 7% and 5.5% of subjects, respectively. 
Visible, grade 2 ulceration, abscess formation and fistulas with granulomatous inflammation 
have been observed for approximately 24 months after vaccination, particularly in patients with 
pre-malignant disease. In addition, a significant number (~10-20%) of patients with pre- 
malignant disease have reported fatigue, fever and chills of up to CTC grade 3. For details see 
the ISA101-101b Investigator Brochure (21). 
 
Local swelling and discoloration of different size and intensity has persisted for a prolonged 
period (one year or more) in the majority of patients who have received HPV-16-SLP in 
Montanide. In some cases these complaints require specific treatment of the vaccination site 
by a dermatologist. In some patients, local excision led to alleviation of the symptoms. Long 
term follow up for up 12 months of the first VIN study (P88/89) revealed visible or palpable 
lesions in about 75% of the patients; about half of the biopsies showed a granulomatous 
inflammatory reaction, sometimes resulting in the formation of scar tissue. 
 
In addition to local reactions, systemic allergic reactions leading to study withdrawal have been 
reported in approximately 7% of patients who have received HPV-16-SLP. One patient also 
reported difficulty in breathing. Patients have responded to an anti- histamine, in those 
instances when it was given.  Vaccinations should therefore only be administered in a clinic 


2017-0145 
March 20, 2018 
 
12 
 
 
 
 
where immediate treatment of severe allergic reactions is possible. 
 
An odorous breath lasting up to approximately > 24 hours, most likely due to the DMSO 
component in the vaccine formulation, was also a frequently reported side effect. 
 
Table 1. HPV-16-SLP safety overview in malignant diseases; local injection site 
reactions 
Malignant diseases (N=69) 
Range (x-y%) - severity grade 
 
Grade 1 (%) Grade 2 (%)Grade 
3 
Grade1: 29-31% 
Erythema 
25-27 
29-31 
0 
 
Grade 2: 69-70% 
Grade 3: 0% 
Pain 
96-98 
2-4 
0 
Induration or 
48-50 
35-37 
0 
Nodules 
NA 
 
 
Ulceration 
NA 
 
 
Itching 
25-27 
7-8 
0 
Pigmentation 
NA 
 
 
 
 
Table 2. HPV-16-SLP safety overview in malignant diseases; systemic reactions, 
withdrawals and SAEs 
 
Malignant diseases (N=69) 
Systemic 
reactions (%)* Max 
Withdrawals 
(number, 
reasons)
SAE** 
(number, 
type)
 
Grade 
1 (%) 
Grade 
2 (%) 
Grad
e 3(%) 
 
 
Fever 
Chills 
Malaise 
Nausea 
Vomitin
10-12 
17-19 
9-11 
7-9 
2-3 
10-12 
0 
2-3 
0 
0 
0 
0 
0 
0 
0 
N=3 
1 death duo to 
local recurrence 
1 inconvience 1 
systemic side 
effect 
N=0 
Dizziness 
1-2 
0 
0 
s Rash 
9-10 
1-2 
0 
Headach 
0 
2-3 
0 
e Fatigue 
10-12 
3-4 
0 
Flu like symptoms 
9-11 
3-4 
0 
Tingling 
2-3 
0 
0 
extremities 
6-8 
0 
0 
Swelling 
1-2 
0 
0 
extremities 
0 
2-3 
0 
* 34 patients died in the Phase I End‐stage CxCA study in the follow‐up phase between 2‐17 months, due to PD. 
** 
In study CHDR0919, the pilot chemo-immunotherapy study (N=18 of which 6 patient did not receive vaccination), 7 
SAEs in 7 patients were reported: 2 deaths due to metastatic disease (one received HPV-16-SLP vaccination); 4 complications 
as result of advanced oncological disease (3 received HPV-16-SLP vaccination); 1 complication with standard treatment of 
oncological disease (no HPV-16-SLP vaccination). Other adverse event data from this study are not yet available. 
 
For a more detailed description of the local and systemic side effects in the various studies 
with HPV-16-SLP, see ISA101-ISA101b Investigator’s Brochure (21). 
 
The vegetable sourced adjuvant Montanide is based on mineral oil and is a more pure form of 
mineral oil than Freund’s incomplete adjuvant (IFA). It is an adjuvant that non- specifically 


2017-0145 
March 20, 2018 
 
13 
 
 
 
 
induces an immune response and functions as a depot for the peptides, to assure a slow and 
consistent release. In preclinical mouse experiments the adjuvants IFA or Montanide were 
shown to be safe and to support robust anti-T cell immunity induced by long peptides. 
 
In this study Montanide will be used for emulsification of the peptides before injection, resulting 
in a formulation of DMSO/WFI/Montanide of 20/30/50%. The dose level of ISA101b peptides 
is 100 micorgams/peptide and is based on available data from the CervISA trial. In clinical 
trials conducted previously, HPV-16-SLP was also formulated in DMSO/WFI (or 
PBS)/Montanide 20/30/50%, and administered at the same highest dose and same volume of 
Montanide. 
 
The subcutaneous route of administration has been used in the preclinical experiments in rats 
and rabbits conducted by ISA Pharmaceuticals B.V. (ISA). These repeated dose toxicology 
studies involved dosing the vaccine reconstituted and emulsified in DMSO and Montanide in 
the same manner as proposed for the clinic. In both species the vaccine was well tolerated 
systemically after repeated s.c.  administration although local inflammation at the site of 
injection could be attributed to the adjuvant Montanide [Investigator’s Brochure, Montanide ISA 
51 VG, August 2013]. 
 
Although the use of the adjuvant Montanide has been associated with a number of side effects, 
most notably of a local nature, the evidence that this adjuvant is needed for robust T cell 
response induction by ISA101 is strong and the side effects are considered acceptable for a 
therapeutic vaccine modality that is capable of the induction of vigorous T cell immune 
responses against HPV-16 E6/E7 in patients with HPV induced malignancies. 
 
1.4.4.3 Antitumor activity summary 
Clinical experience with ISA101, per se, is limited as clinical studies were initiated in June 
2013. 
 
C ervISA: An open label phase I/II study in patients with advanced or metastatic (stage IVb) 
or recurrent HPV-16 positive cervical cancer for whom no curative treatment options exist. 
This is a sequential group study of patients who have advanced (stage IIIb-IVa with involvement 
of lymph nodes beyond the renal vein) or metastatic (stage IVb) or recurrent HPV-16 positive 
cervical cancer for whom no curative treatment options exist. All subjects will receive ISA101 
in Montanide by subcutaneous injection at the dose levels described in Table 1. The study 
was designed to enroll cohorts of six patients each to evaluate the safety and HPV-specific 
immune responses following different vaccination 
regimens. Patients will receive 
chemotherapy considered standard of care for this disease: starting with carboplatin at an AUC 
of 6 plus paclitaxel at a dose of 175 mg/m2 dose reductions in chemotherapy are allowed, 
consistent with the standard of care, with continuation of vaccination (with or without pegylated 
IFNα, depending on the assigned cohort). The maximum total treatment duration for a patient 
is six cycles (1 cycle is 21 days) of carboplatin and paclitaxel for a total of 18 weeks, if there 
are no dose interruptions or delays. On Day 15 (±3 days) of cycles 2, 3 and 4, the vaccination 
scheme of ISA101 with or without pegylated IFNα (depending on cohort assignment in Table 
1) will start. The patients will be vaccinated with a fixed dose of ISA101 every three weeks for 
a total of three ISA101 vaccinations. Four dose levels of ISA101 may be assessed. 
 
The primary endpoints of the study are safety and HPV-specific immune responses. The 
secondary endpoints are antitumor efficacy according to RECIST 1.1 (overall response rate, 
disease control rate, progression free survival). Exploratory endpoints include general 
responsiveness of the immune system. As of May, 2014, only the first cohort was evaluated, 
and patient recruitment is ongoing. The AEs and SAEs observed to date appear to be 
expected complications of advanced cervical cancer and/or standard chemotherapy. Virtually 


2017-0145 
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14 
 
 
 
 
all of the AEs and SAEs that are reported as “related" to the protocol-specified therapy (e.g. 
thrombocytopenia, neutropenia, anemia), are expected complications of chemotherapy. No 
new or unexpected safety concerns potentially related to ISA101 have been identified in this 
ongoing study to date. 
 
VACCAIN1: A study of ISA101 administered by intradermal injection without Montanide in 
patients with Anal Intraepithelial Neoplasia (AIN). Study ISA101- AIN is an investigator 
initiated study, which is designed to assess therapeutic vaccination against HPV-16 with 
ISA101 for the treatment of anal intraepithelial neoplasia in HIV- positive (HIV+) men. It should 
be noted that this study is being conducted using ISA101 without Montanide administered by 
intradermal (i.d.) injection. The Academic Medical Center in Amsterdam has started a 
sequential group dose-response study with ISA101 in HIV-positive MSM, with 3 different 
dosage schedules, based on intra-patient dose escalation: schedule I: 1,5,10 µg, schedule II: 
5,10,20 μg and schedule III: 10,20,40 μg of ISA101 administered i.d. with a three-week 
interval. Each dosage schedule will be evaluated with or without the co-administration of 
pegylated interferon-α (Pegintron 1 μg/kg s.c.) on the day of vaccine administration. Each 
vaccination schedule is to be tested in 5 patients. The vaccination regimen that induces the 
best HPV-16-specific response with an acceptable safety profile will be considered the optimal 
schedule in this clinical setting. The size of this dose group will be increased to a total of 20 
patients by vaccinating an additional 15 patients. 
Data developed with HPV-16-SLP may inform the development of ISA101 with respect to 
mechanism of action, the safety profile and biologic activity. However, due to changes in 
manufacturing and analytical methods, HPV-16-SLP and ISA101 are considered different 
products from a regulatory point of view. The clinical trials described below are all investigator- 
sponsored studies of the prototype vaccine HPV-16-SLP. As summarized in the following 
tables, multiple studies evaluating HPV-16-SLP vaccination have been conducted in the past. 
These studies using HPV-16-SLP have included patients with different types of high-risk pre- 
malignant and malignant HPV-induced diseases (Table 3). 
 
Table 3. HPV-16-SLP vaccination clinical trials. 
Study ID 
Indication 
Study design 
Key (immunological) results 
Pre-malignant diseases 
P88/89 
Phase II 
High-grade VIN 
22 patients: 4 
vaccinations at 3 
week interval 
Clinical responses in women with HPV-16 
positive, grade VIN3, correlated with 
induction of HPV-16 specific immunity (1). 
P06.227 
Phase II 
High-grade CIN 
9 patients (planned 
50): 
Two 
arms, 
placebo controlled, 
at 
3 week interval 
Vaccination of HSIL patients results in 
increased 
HPV-16- 
specific 
T-cell 
immunity. (43). 
Study was terminated after 9 of planned 50 
patients were recruited, due to lack of 
recruitment. 
P06.226 
Low-grade CIN or 
persistent PAPII 
50 patients: 4 
vaccinations at 3 
week interval, three 
arms, 
placebo 
controlled 
Robust  HPV-16-specific  T-cell responses 
detected after vaccination (44). 
 
Study ID 
Indication 
Study design 
Key (immunological) results 


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15 
 
 
 
 
P08.062 
Phase II 
High-grade VIN or 
VaIN 
39 patients: Two 
arms, 4 vaccinations 
at 3 week interval 
Patients with  high-grade  VIN  (or  VaIN) 
Analysis is pending. 
Malignant diseases 
P88/89 
Phase I 
End-stage cervical 
cancer 
43 patients: 4 
vaccinations 
at 
3 
week interval 
The vaccinations resulted in a strong and 
broad T-cell response (2). 
P88/89 
Phase II 
FIGO stage 1B1 
cervical cancer 
6 patients: 4 
vaccinations 
at 
3 
week interval 
The HPV-16 E6 and E7 SLP increases the 
number and activity of HPV-16-specific CD4(+) 
and CD8(+) T-cells to a broad array of epitopes 
in all patients (45). 
P05.086 
Phase II 
End-stage 
gynecological cancer 
20 patients: 4 
vaccinations 
at 
3 
week interval 
The HPV-16-SLP vaccine induced a broad 
IFNγ-associated T-cell response in patients 
with advanced or recurrent HPV-16-induced 
gynecological carcinoma but neither induced 
tumor regression nor prevented progressive 
disease (15). 
CHDR0912 
Pilot 
chemo- 
immuno 
therapy 
Advanced or recurrent 
cervical cancer where 
carboplatin/paclitaxel is 
appropriate 
18 patients: 
6 
patients 
carboplatin/paclitaxel 
only 
12 
patients 
vaccinated on D15 of 
cycle 
2 
of 
carboplatin/paclitaxel 
Interim analysis 
a   single   vaccine   dose   of   HPV-16-SLP 
+Montanide  could 
induce  strong  T  cell 
responses 
if   the   timing 
in   relation   to 
chemotherapy delivery was optimized (46) 
and unpublished observations). 
 
1.4.5  Utomilumab: Clinical Results 
An ongoing phase 1 trial of utomilumab, alone in patients with mixed solid tumors, or in 
combination with rituximab for patients with CD20+ non-Hodgkin’s lymphoma, has accrued 
86 patients with mixed solid tumors as of June 2016 (NCT01307267). Dose levels from 0.006 
mg/kg to 10 mg/kg i.v. every 4 weeks have been studied. The most frequently observed 
treatment-emergent adverse  event  (TEAE) (≥ 10%  of  patients;  all grades)  was fatigue 
(11.6%). TEAEs were mostly grade 1-2 with 3 grade 3 AEs (ALT elevation, fatigue, and 
hyponatremia). Causality of the grade 3 ALT elevation was ultimately assessed by the 
investigator as not related to utomilumab. Three treatment-related SAEs were reported in 2 
patients: enterocolitis, decreased appetite, and pneumonitis. One patient permanently 
discontinued treatment for grade 2 treatment-related enterocolitis. Uncommon grade 1-2 
TEAEs included cough, headache, and decreased lymphocyte count in anemia, dizziness, 
fatigue, muscle spasm, nausea/ vomiting, pyrexia and rash. Significantly, and in contrast to 
another anti-CD-137 antibody, urelumab (BMS663513), no hepatotoxicity related to 
utomilumab has been observed. (8) (9) (19). In the 47 pts in the lymphoma cohort, most 
frequent TEAEs were fatigue (23%) and infusion reactions (21%). TEAES related to 
utomilumab were either grade 1 or 2 in severity and none led to treatment discontinuation. 
 
Efficacy signals in the solid tumor cohort of the above trial have been limited to the lower dose 
levels (0.3 - 2.4 mg/kg). Specifically with utomilumab mono-therapy, two patients with Merkel 
cell carcinoma attained CR and PR at 0.24 and 0.6 mg/kg, respectively and one patient with 
melanoma attained PR. Notably, only one patient with head and neck cancer has been 
treated.  In the lymphoma cohort, 8 patients with follicular lymphoma achieved CR (4) or PR 
(4) and one patient each with Hodgkin’s lymphoma and Mantle Cell lymphoma achieved PR. 


2017-0145 
March 20, 2018 
 
16 
 
 
 
 
Pharmacokinetic data from 68 patients receiving doses from 0.006 to 5 mg/kg showed that 
only 7% of inter-patient variability was related to body weight. In addition, simulations 
indicated that exposure was similar between body weight-based and fixed dosing regimens. 
 
A phase I trial of utomilumab and pembrolizumab accrued 23 patients. The most frequent 
treatment-related AEs were fatigue (35%), rash (26%) pruritus (22%), pyrexia (17%), nausea, 
decreased appetite, dry skin and mouth (13% each). Treatment-related AEs were mostly 
grade1 or 2. Grade 3 events in 2 pts were adrenal insufficiency and hypokalemia. No patients 
discontinued treatment due to toxicity. There were no treatment-related grade 4 or 5 AEs or 
deaths. There were no DLTs, clinically significant EKG or vital signs changes reported. 
Efficacy signals included 6 patients with CR or PR (small cell lung cancer, head and neck 
cancer, renal cell cancer (2 pts), anaplastic thyroid cancer, and non-small cell lung cancer. 
 
 Evolving data from an ongoing trial with utomilumab in combination with other immune 
checkpoint modulators suggests that response in PD-1/L1 treated patients is infrequent. Thus, 
our trial will include only patients who are naïve to PD-1/L1 inhibitors, and  platin-resistant,  
the population for whom PD-1 inhibitors are currently indicated by the FDA.  
 
1.5 Overall Risk/Benefit Assessment 
Subjects with recurrent/metastatic incurable HPV-positive oropharyngeal and anogenital tract 
cancers represent a population for whom immunotherapy holds potential that has yet to be 
realized. HPV-16-SLP, the precursor vaccine to ISA 101, induced HPV-16 proliferative T cell 
responses in approximately 50% of patients with end-stage gynecological cancers, but did not 
cause any objective tumor regression. These data provide rationale to pursue combination 
strategies to amplify immune response. 
 
Similarly, the 16% ORR to both nivolumab and pembrolizumab (1,2) with anti- PD-1 therapy 
in platin-refractory HPV-positive OPSCC demonstrates the promise of this approach, and at 
the same time, the need to pursue relevant combinations. In a recently completed  trial we 
have studied the combination of ISA-101 with nivolumab with objective response in 8/22 
(36%) patients with recurrent HPV-16 + OPSCC, doubling the rate of response expected from 
nivolumab alone (3).  The OS from this trial is also quite promising with a median OS of 17.5 
mos, and a randomized trial is planned to confirm these findings.  The trial of utomilumab and 
ISA101b is  the second trial in our HPV-related Moon Shot project to study rational 
immunotherapy combinations for HPV-related cancers. While this combination builds on our 
own preclinical data and its clinical translation is clearly a high priority, we envision its 
greatest value will be as a foundational regimen on which to add other checkpoint modulators  
for these virally driven cancers. For example, the correct sequencing of utomilumab and αPD-
1/L1 therapy is being studied both in syngeneic models and clinically, possibly prelude to the 
next trial in our series.. 
 
ISA 101 has been very well-tolerated with injection site reactions the most common AE. 
Systemic reactions, typically readily manageable with anti-histamines or steroids, have also 
been observed, but typically at 300 mcg/peptide.  The combination of ISA101 and nivolumab 
has been very well tolerated in 24 patients of our ongoing trial with mainly grade 1 toxicity and 
only two  grade 3 enzymye elevations (one hepatic, one pancreatic)  that quickly resolved 
when treatment was held.   Given the excellent tolerance for both ISA101 and utomilumab 
as monotherapy, we predict good tolerance for the combination. To assure safety, we will 
continuously assess toxicity in cohorts of 4 subjects (section 6.3.4) throughout the conduct of 
the trial. 
 
Accrual rate: The ISA101/nivolumab trial  accrued 24 pts/12 months and we predict a similar 
rate of 2 pts/month and completion of accrual in ~ 1 year. 


2017-0145 
March 20, 2018 
 
17 
 
 
 
 
 
Depending upon the results of treatment in OPSCC patients and additional clinical experience 
with utomilumab amendments may be issued to study other doses of utomilumab and/or 
accrue expansion cohorts of patients with HPV-16 + anogenital cancers. 
 
 
 
 
2.0 Investigational Plan 
 
2.1 Study Design and Duration: 
This is a single arm  Phase 2 study in adult (≥ 18 years old) male and female subjects 
with platin-refractory (recurrence on or within 6 mos of platin treatment in definitive or palliative 
setting), PD-1/L1 inhibitor naïve, recurrent/ metastatic HPV+ OPSCC. Patients could have 
received up to two prior regimens for recurrent cancer. 
 
We will evaluate  ISA101b and utomilumab at doses which have previously proven safe in 
completed and ongoing trials (i.e., 100 ug/peptide ISA101, 50- 100 mg utomilumab).(Figure 2 
and 3).  Toxicity monitoring (CTCAE v4.03) (Section 6.2) will be in groups of 4 patients. The 
DLT window will be 2 cycles (8 wks) of utomilumab. For details see section 6.3.4. 
 
 
 
 
Figure 2: Utomilumab + ISA101b Trial Design 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ISA101b vaccine 
Dose #1                      Dose #2                   Dose #3 
D1 
Dose #1                      Dose #2                   Dose #3               q. 4 wk to PD or C12 
 
               Utomilumab  
D29 
D57 
 
 Biopsies and Imaging 
• 
ISA101b  sc at 100 mcg/peptide in Montanide adjuvant for 3 doses, q 4 wks 
• 
Utomilumab administered i.v.  q 4 wks  C1-2 100 mg,  C3-12 50 mg  until PD, toxicity, or 1 yr 
• 
Imaging: baseline and  q 8 wks 
• 
Biopsies: baseline, restaging at 8 wks, on progression 
• 
Blood: baseline, pre-vaccine doses 2 and 3, prior to utomilumab C 4, C 8, C12 or at PD.  


2017-0145 
March 20, 2018 
 
18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: Utomilumab+ ISA101b Treatment Schedule 
 
 
Subjects will undergo screening evaluation to determine eligibility within 28 days prior to trial 
inclusion. A cycle is 4 weeks in duration. The primary endpoint is objective response rate 
with a target ORR ≥ 30%. Response and progression will be evaluated in this study using 
the new international criteria proposed by revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline version 1.1 (Appendix 1). 
 
 
This study will consist of 3 phases: screening (Table 5), treatment (Table 6), and follow- up 
(Table 7). 
 
This study will end when analysis of survival is complete. Including follow-up, duration of 
the trial will be ~3 years. 
 
 
2.2 Study Population 
For entry into the study the following criteria must be met: 
 
2.2.1 Inclusion Criteria 
 
1) Signed Written Informed Consent 
a) Subjects must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
subject care. 
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests and other requirements of the study. 
 
2) Target Population 
a. Men and women ≥ 18 years of age 
b. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 
c. Subjects with histologically- or cytologically-documented incurable Human Papillomavirus 
(HPV)-positive OPSCC. HPV-16 serotype will be assessed by Cervista assay (Section 4.1.1) 
d. Subjects can be treatment naïve or may have had two prior regimens for recurrent 
cancer. They must be naïve to treatment with  PD-1/L1 or CTLA-4  inhibitors. 
e. Subjects must have progression within 6 mos of platin exposure  during definitive or 
palliative therapy  
f. Subjects must have measurable disease by CT or MRI per RECIST 1.1 criteria; 
Radiographic Tumor Assessment performed within 28 days of study inclusion. 
g.Target lesions may be located in a previously irradiated field if there is documented 
(radiographic) disease progression in that site. 


2017-0145 
March 20, 2018 
 
19 
 
 
 
 
h. Subject entering the study will need to consent for mandatory biopsy at study entrance 
and as an optional procedure prior to C3 for biomarker evaluation 
4. Biopsy should be excisional, incisional or core needle. Fine needle aspiration is 
insufficient. 
i. Prior chemotherapy, , monoclonal antibody therapy, must have been 
completed at least 4 weeks prior to start.  Radiotherapy or radiosurgery must have been 
completed at least 2 weeks prior to start. 
j. All baseline laboratory requirements will be assessed and should be obtained within -14 
days of study registration. Screening laboratory values must meet the following criteria 
i) WBCs ≥ 2000/microL 
ii) Neutrophils ≥ 1500/microL iii) Platelets ≥ 100 x 10³/microL iv) Hemoglobin ≥ 
9.0 g/dL Patients must not be transfused for at least 14 days prior to study entry 
v) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance > 50 mL/minute (using 
Cockcroft/Gault formula) 
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 
vi) AST ≤ 2.5X ULN 
vii) ALT ≤ 2.5X ULN 
viii) Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome who must have total 
bilirubin <3.0 mg/dl) 
 
3) Age and Reproductive Status 
a) Women of childbearing potential (WOCBP) must use method(s) of contraception for  30 
days + 5 half-lives (60 days) of the study drugs.  For a teratogenic study drug and/or when 
there is insufficient information to assess teratogenicity (preclinical studies have  not been 
done), a highly effective method(s) of contraception (failure rate of less than 1% per year) 
is required. Highly effective birth control in this study is defined as a double barrier method.
 
Examples include a condom (with spermicide) in combination with a diaphragm, cervical 
cap, or intrauterine device (IUD). The individual methods of contraception should be 
determined in consultation with the investigator. 
b) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L 
or equivalent units of HCG) within 24 hours prior to the start of investigational product. 
c) Women must not be breastfeeding 
d) Men who are sexually active with WOCBP must use any contraceptive method with a 
failure rate of less than 1% per year. The investigator shall review contraception methods 
and the time period that contraception must be followed. 
Men that are sexually active with WOCBP must follow instructions for birth control for a period 
of 90 days plus the time required for the investigational drug to undergo 5 half- lives (60 days). 
 
2.2.2 Exclusion Criteria 
 
1) Target Disease Exceptions 
a. Subjects with active CNS metastases are excluded. Subjects are eligible if CNS 
metastases are adequately treated and subjects are neurologically returned to baseline 
(except for residual signs or symptoms related to the CNS treatment) for at least 4 weeks 
prior to enrollment. In addition, subjects must be either off corticosteroids, or on a stable or 
decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for 2 weeks. 
b. Subjects with carcinomatous meningitis. 


2017-0145 
March 20, 2018 
 
20 
 
 
 
 
 
 
2) Medical History and Concurrent Diseases 
a. Subjects with active, known or suspected systemic autoimmune disease. Subjects with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only 
requiring hormone replacement, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll. 
b. Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of start. 
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone 
equivalent, are permitted in the absence of active autoimmune disease. 
c. Prior therapy with anti-CD137or ISA101. 
d. Subjects with a history of interstitial lung disease. 
e. Other active malignancy requiring concurrent intervention. 
f. Subjects with previous malignancies (except non-melanoma skin cancers, and the following 
in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) 
are excluded unless a complete remission was achieved at least 2 years prior to study entry 
AND no additional therapy is required during the study period 
g. Subjects with toxicities attributed to prior anti-cancer therapy other than alopecia and 
fatigue that have not resolved to grade 1 (NCI CTCAE version 4.03) or baseline before 
administration of study drug. 
h. Subjects who have not recovered from the effects of major surgery or significant 
traumatic injury at least 14 days before the first dose of study treatment. 
i. Treatment with any investigational agent within 28 days of first administration of study 
Treatment. 
 
3) Physical and Laboratory Test Findings 
a) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). 
b) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus 
ribonucleic acid (HCV RNA) indicating acute or chronic infection. 
 
 
 
4) Allergies and Adverse Drug Reaction 
History of allergy or intolerance (unacceptable adverse event) to study drugs components. 
 
5) Sex and Reproductive Status 
a) WOCBP who are pregnant or breastfeeding 
b) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication 
 
6) Other Exclusion Criteria 
a) Any other serious or uncontrolled medical disorder, active infection, physical exam finding, 
laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the 
investigator, would limit a subject’s ability to comply with the study requirements, substantially 
increase risk to the subject, or impact the interpretability of study results. 
b) Prisoners or subjects who are involuntarily incarcerated. 
c) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness 


2017-0145 
March 20, 2018 
 
21 
 
 
 
 
 
 
2.2.3 Women of Childbearing Potential 
A Woman of Childbearing Potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy  or bilateral 
oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of 
amenorrhea in a woman over age 45 in the absence of other biological or physiological causes. 
 
2.3 Concomitant Treatments 
2.3.1 Prohibited and/or Restricted Treatments 
The following medications are prohibited during the study (unless utilized to treat a drug- 
related adverse event): 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 
2.3.3). 
• Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, extensive, radiation therapy, or standard or investigational agents) 
 
Palliative and supportive care for disease related symptoms (including local radiotherapy, 
bisphosphonates and RANK-L inhibitors) may be offered to all subjects prior to first dose of 
study therapy (prior radiotherapy must have been completed at least 2 weeks prior to start). 
 
2.3.2 Other Restrictions and Precautions 
Subjects with active, known or suspected systemic autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring 
hormone replacement, or conditions not expected to recur in the absence of an external trigger 
are permitted to enroll. 
 
Subjects are excluded if they have a condition requiring systemic treatment with either 
corticosteroids (>10mg daily prednisone equivalent) or other immunosuppressive medications 
within 14 days of start.  Inhaled or topical steroids, and adrenal replacement steroid doses > 
10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease. 
 
 
 
2.3.3 Permitted Therapy 
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of 
systemic corticosteroids (eg, prednisone ≤ 10 mg/day) are permitted. A brief (less than 3 
weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of 
non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by a contact 
allergen) is permitted. 
 
The potential for overlapping toxicities with radiotherapy and utomilumab or ISA 101 currently 
is not known. Therefore, palliative radiotherapy is not permitted while receiving the study 
drugs.  
 
2.4 Discontinuation of Subjects from Treatment 
Subjects MUST discontinue investigational products at the discretion of the investigator for 
any of the following reasons: 


2017-0145 
March 20, 2018 
 
22 
 
 
 
 
 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
 
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject 
 
Pregnancy 
 
Termination of the study 
 
Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness 
Additional protocol-specific reasons for discontinuation (See Section 3.3.5) 
 
All subjects who discontinue should comply with protocol specified follow-up and survival 
procedures as outlined in section 4.2.2. The ONLY exception to this requirement is when a 
subject withdraws consent for all study procedures or loses the ability to consent freely (ie, 
is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical 
illness). 
 
3.0 Treatments 
 
3.1 Study Treatments 
The Investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational products ISA101b and utomilumab in accordance with the protocol and any 
applicable laws and regulations. 
 
 
Investigational product documentation must be maintained that includes all processes required 
to ensure study drug is accurately administered. This includes documentation of study drug 
storage, administration and, as applicable, storage temperatures, re- constitution, and use of 
required processes (e.g. required diluents, administration sets). 
 
Recommended safety measures for preparation and handling of utomilumab and ISA101b 
include laboratory coats and gloves. 
 
3.2 Handling and Dispensing 
Utomilumab (PF095082566) will be supplied for the study by Pfizer Global Clinical 
Supply, Worldwide Research and Development. Drug supplies will be shipped with Drug 
Shipment and Proof of Receipt form. This form will be completed, filed, and shipment 
confirmed as directed on the form. 
 
Utomilumab is a sterile, colorless solution intended for IV administration. It is presented at 
a concentration of 10 mg/mL with a nominal volume of 10 mL in glass vials closed with a 
rubber stopper and sealed with an aluminum overseal.  The vial is intended for single use 
only. PF-05082566 will be shipped in transport cool containers (2C to 8C) that are monitored 
with temperature control monitoring devices. 
 
See the dosage and administration instructions section of the Utomilumab Investigational 
Product Manual for instructions on preparation for administration. 
 
Utomilumab will be given by i.v. infusion over one hour once every 4 weeks on Day 1 of each 
cycle. 
 
Utomilumab must not be used for any purpose other than the trial. 
 


2017-0145 
March 20, 2018 
 
23 
 
Any unused portion of the solution should be discarded in biohazard waste disposal with final 
disposal by accepted local and national standards of incineration. 
  
 
ISA101b and montanide will be shipped by ISA with Drug Shipment and Proof of 
Receipt form. 
 
ISA101b is a lyophilized powder of the two peptides/drug products which must be stored in 
glass vials in the dark at ‐20°C as specified in the pharmacy manual. ISA101b vaccine will be 
packaged in an open-label fashion. 
 
 
The ISA101b vaccine contains nine HPV-16 E6 and three HPV-16 E7 SLP. For technical 
details reference is made to the IB (21). The peptides are dissolved in dimethylsulfoxide and 
subsequently diluted in WFI and emulsified with Montanide as detailed in the pharmacy 
manual. The final ratio of dimethylsulfoxide / WFI / Montanide is 20/30/50. 
 
The vaccine will be injected in two s.c. injections, containing the two HPV-16 SLP products, in 
two anatomically distinct locations (e.g., one in an upper, and one in a lower extremity). 
The 
final 
formulation 
for 
s.c. 
administration 
consists 
of 
20/30/50 
v/v/v-% 
DMSO/WFI/Montanide. 
 
The maximum recommended hold time between ISA101b vaccine preparation and 
administration is 2 hours. Care must be taken to assure sterility of the prepared solution as 
the product does not contain any anti-microbial preservative or bacteriostatic agent. 
 
3.3 Selection and Timing of Dose/Dose Reduction 
Utomilumab will be given intravenously for approximately 60 minute IV infusion, on Day 1 of 
a treatment cycle every 4 weeks. . Utomilumab may be held for persistent toxicity as detailed 
in the next section. There are no premedications recommended for utomilumab on the first 
cycle. If an acute infusion reaction is noted, subjects should be managed according to Section 
3.3.6. 
 
ISA101b will be administered at 3 specific time points, on day 1 of the first 3 treatment cycles 
(Day1, 29 and 57). On each occasion it will be administered as two s.c. injections (one injection 
for each set of peptides) in two anatomically distinct locations (e.g. one injection in an upper 
extremity and the other in a lower extremity or one in each upper extremity with different sites 
used for each at each specified ISA101b vaccination timepoint). Dose of ISA 101b will be 100 
mcg per peptide. 
 
Utomilumab infusion will precede ISA101b vaccination. Patients should be observed for 
approximately one hour following completion of utomilumab infusion prior to ISA101b 
vaccine. Post vaccination patients are observed for 3 hrs. 
 
 
 
3.3.1 Dose Delay Criteria 
Tumor assessments for all subjects should continue as per protocol even if dosing is 
interrupted. 
 
3.3.1.1 Investigational Drugs Dose Delay Criteria 
Utomilumab and/or ISA101b administration should be delayed for the following: 
• 
Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 
– Grade 2 drug-related fatigue that does not require a treatment delay 
• 
Any Grade ≥ 3 skin, drug-related adverse event 


2017-0145 
March 20, 2018 
 
24 
 
 
 
 
• 
Any Grade ≥ 3 drug-related laboratory abnormality, with the following exceptions 
for lymphopenia, leukopenia, AST, ALT, or total bilirubin: 
– Grade ≥ 3 lymphopenia or leukopenia does not require dose delay 
– Asymptomatic Grade 3/4 increase in amylase/lipase does not require dose 
delay 
– If a subject has a baseline AST, ALT or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥ 2 toxicity 
– If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥ 3 toxicity 
• 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
 
3.3.2 Dose Reductions 
There are no dose reductions for toxicity from Utomilumab or ISA101b 
 
3.3.3 Criteria to Resume Dosing 
3.3.3.1 Criteria to Resume Treatment with utomilumab 
Subjects may resume treatment with utomilumab when the drug-related AE(s) resolve(s) to 
Grade ≤ 1 or baseline, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity 
• 
Subjects with baseline AST/ALT or total bilirubin in the Grade 1 toxicity range who 
require dose delays for reasons other than a 2-grade shift in AST/ALT or total  bilirubin 
may resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin 
• 
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 3.3.5) should have treatment permanently 
discontinued 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. Drug-related endocrinopathies adequately controlled 
with only physiologic hormone replacement may resume treatment 
• 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from 
study therapy, except as specified in Section 3.3.5. 
 
 
 
3.3.3.2 Criteria to Resume Treatment with ISA101b 
Subjects may resume treatment with ISA101b when the drug-related AE(s) resolve(s) to 
Grade ≤ 1. 
 
3.3.4 Treatment 
After 
Initial 
Evidence 
of 
Radiological 
Disease 
Progression 
Immunotherapeutic agents such as utomilumab may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
 
If radiologic imaging shows disease progression, tumor assessment should be repeated ≥4 
weeks later in order to confirm the observation. Assigned study treatments may be continued 
at the Investigator’s discretion while awaiting radiologic confirmation of disease progression. 


2017-0145 
March 20, 2018 
 
25 
 
 
 
 
Patients may receive study treatments while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria: 
 
 
Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression. 
 
No decline in ECOG performance status. 
 
Absence of rapid progression of disease by radiographic imaging. 
 
Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention. 
 
If patients are treated beyond progression as above, documentation of discussion with the 
subject regarding this action should be documented in the medical record. 
 
If repeat imaging no longer shows PD but rather CR, PR or stable disease (SD) compared to 
the initial scan, treatment may be continued/resumed. In determining whether or not the tumor 
burden has increased or decreased, Investigators should consider all target as well as non- 
target lesions. If the repeat imaging confirms PD, patients should be discontinued from the 
trial. 
 
3.3.5 Treatment Discontinuation Criteria 
Utomilumab should be discontinued for grade ≥ 3 hematologic/non-hematologic toxicity with 
the following EXCEPTIONS: 
 
Transient (≤6 hours) flu-like 
 
symptoms or fever, which is controlled with medical management. 
 
Transient (≤24 hours) fatigue, local reactions, headache that resolves to Grade ≤1. 
 
Nausea and vomiting controlled by medical therapy 
 
Diarrhea, skin toxicity, or liver function test (ALT, AST, or GGT) that resolves to ≤ 
Grade 1 in less than 7 days after medical management (eg,immunosuppressant 
treatment) has been initiated. 
 
Amylase or lipase abnormality that is not associated with symptoms or clinical 
manifestations of pancreatitis. 
 
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor. 
 
Non hematologic laboratory abnormality that does not require medical intervention or 
hospitalization 
 
Single non hematologic laboratory values that do not have any clinical correlate, and 
resolve to ≤ Grade 1 within 7 days with adequate medical management 
 
Permanent discontinuation is indicated for grade 4 toxicity with the following EXCEPTIONS: 
 
Non hematologic laboratory abnormality that does not require medical intervention or 
hospitalization. 
 
Single non hematologic laboratory values that do not have any clinical correlate, and 
resolve within 7 days with adequate medical management. 
 
3.3.6 Management of Infusion-Related Reactions 
Since utomilumab is a monoclonal antibody and is administered IV, infusion-related reactions 
may occur (with symptoms such as fever, chills, rigors, diaphoresis, and headache). 
Treatment of the infusion-related reaction and modifications of the infusion(s) are 
mainly dependent upon severity, as indicated in Table 4: 


2017-0145 
March 20, 2018 
 
26 
 
 
 
 
Table 4.   Treatment Modification for Symptoms of Infusion-Related Reactions 
 
NCI CTCAE Grade 
Treatment Modifications 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease the investigational product infusion 
rate by 50% and monitor closely for any 
worsening. The total infusion time should not 
exceed 120 minutes. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds 
promptly 
to 
symptomatic 
treatment 
(eg, 
antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for 
4 hours. 
Stop investigational product infusion. 
Resume infusion at 50% of previous rate as 
soon as infusion-related reaction has resolved 
or decreased to at least Grade 1 in severity, 
and monitor closely for any recurrence or 
worsening. 
Grade 3 or Grade 4 – severe or life- 
threatening Grade 3: Prolonged (eg, not 
rapidly responsive to symptomatic medication 
and/or brief interruption of infusion); recurrence 
of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
Grade 
4: 
Life-threatening 
consequences; 
urgent intervention indicated. 
Stop the investigational product infusion 
immediately and disconnect bag infusion 
tubing from the patient. 
 
Investigational product treatment 
must be permanently discontinued. 
IV=intravenous, NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse 
Event, 
NSAIDs=nonsteroidal anti-inflammatory drugs. 
 
Once utomilumab infusion rate has been decreased by 50% due to an infusion-related 
reaction, it must remain so for all subsequent infusions. The total infusion time for utomilumab 
should not exceed 120 minutes. 
 
Additional Modifications for Patients with Grade 2 Infusion-Related Reactions: In the 
event of a Grade 2 infusion-related reaction that does not improve or worsens after 
implementation of the modifications indicated in Table 4 (including reducing the infusion rate 
by 50%), the Investigator may consider treatment with corticosteroids, and the infusion should 
not be resumed for that cycle. At the next cycle, the Investigator may consider the addition of 
H2-blocker antihistamines (e.g., famotidine or ranitidine), meperidine, or ibuprofen to the 
mandatory premedication. Prophylactic steroids are NOT permitted. 
 
3.3.7 Treatment 
of 
ISA101b 
Related 
Systemic 
Reactions 
Systemic allergic reactions up to Grade 2 have been reported in approximately 
7% of patients and have been controlled with antihistamines and/or epinephrine. Patients 
receiving ISA101b in Montanide should be closely monitored for the first 3 hours after 
vaccination. Immediate treatment of severe allergic reactions should be available, including 
staff well-trained in resuscitation, intravenous access for administration of fluids, 
antihistamines and corticosteroids, and epinephrine for intramuscular injection. 
 
3.5 Destruction and Return of Study Drug 
 
3.5.1 Destruction of Study Drug 
For this study, study drugs (those supplied by Pfizer or ISA) such as partially used study drug 
containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible pharmaceutical company unless study drug containers must be immediately 
destroyed as required for safety, or to meet local regulations 
On-site destruction is allowed provided the following minimal standards are met: 


2017-0145 
March 20, 2018 
 
27 
 
 
 
 
• 
On-site disposal practices must not expose humans to risks from the drug. 
• 
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous 
substances. 
• 
Written procedures for on-site disposal are available and followed. The procedures 
must be filed with the site’s SOPs and a copy provided to Pfizer or ISA (as 
appropriate) upon request or termination of the study, all unused and/or partially used 
study drug that was supplied by Pfizer or ISA must be returned to Pfizer or ISA, 
respectively. 
 
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. 
 
4 
ASSESSMENT FOR SAFETY AND EFFICACY 
 
4.1 Safety Assessments 
Safety assessments will be monitored at Screening (Baseline visit), during treatment according 
to the frequency for each treatment starting on Cycle 1 Day 1 and will continue at the specified 
frequency until discontinuation from the study. (See Tables 5, 6, 7) 
 
Table 5. Flow Chart/Time and Events Schedule 
 
Procedure 
Screening 
Visit 
Notes 
Eligibility assessment 
 
 
Informed Consent 
X 
 
Inclusion/Exclusion Criteria 
X 
 
Medical and Tumor History 
X 
 
Safety Assessment 
 
 
Vital Signs and Oxygen 
Saturation 
X 
Temperature, BP, HR, RR, O2 saturation by pulse oximetry 
(also monitor amount of supplemental oxygen if applicable) 
Obtain vital signs at screening visit and within 72 hours of 
first dose 
Physical Exama 
X 
Review of systems including measurements of Height and 
Weight, and ECOG Performance status 
Laboratory Tests 
X 
Labs performed locally within 14 days prior to start of treatment: 
CBC with differential including neutrophil and lymphocyte 
count, 


2017-0145 
March 20, 2018 
 
28 
 
 
 
 
 
 
Serum chemistry (BUN or serum urea  level, serum creatinine, 
sodium, potassium, calcium, magnesium, phosphate, chloride, 
and bicarbonate, glucose), AST, ALT, total bilirubin, alkaline 
phosphatase, albumin, LDH, TSH, free T3, free T4, HBV sAg, 
HCV RNA, HIV1/2 immunoassay 
Cervista assay 
X 
Historical 
result 
or 
assessment 
during 
screening 
acceptable. 
Pregnancy Test 
X 
Performed within 24 hours of registration (serum or urine for 
WOCBP only) 
Procedure 
 
 
Assessment (of signs and 
symptoms) 
X 
After obtaining Informed Consent, assess all signs and 
symptoms within 14 days of study registration, prior to 
study treatment initiation. 
Concomitant Medication 
collection 
X 
Within 14 days of registration 
Efficacy assessments 
 
 
Radiographic 
Tumor 
Assessment (CT or MRI of neck, 
chest, abdomen, pelvis) of all 
known or suspected disease 
sites. 
X 
Should be performed within 28 days of start of treatment. 
CT/MRI of brain (with contrast) should only be performed in 
subjects with a known history of treated brain metastases. 
Known or suspected disease (including CNS) should be imaged 
at the screening visit and at subsequent on- study assessments. 
Biomarker Assessment 
 
 
Mandatory tumor biopsy 
X 
 
a.  Signs and symptoms present within 14 days prior to start of treatment (regardless of 
relationship to disease) will be recorded. 
 
4.1.1 Cervista HPV Assay 
Tumors are required to be HPV-16 positive in order to be eligible. 
 Testing for HPV genotype will be performed with the Cervista assay and conducted according 
to previously published data (38). This assay is not PCR-based but uses proprietary Invader 
chemistry, a signal- amplification method for the detection of specific nucleic acid sequences 
(Hologic, Inc.). The Cervista assay uses oligonucleotide mixtures containing probes specific 
for the L1, E6, and E7 genomic regions of high risk HPV genotypes. Oligonucleotides 
targeting the human histone 2 gene (H2be, HIST2H2BE) serve as an internal control for 
detection of cellular DNA. A signal-to-noise value, referred to as fold over zero (FOZ), is 
determined for each specimen. The FOZ cutoff value for a positive result is 2.13. 


2017-0145 
March 20, 2018 
 
29 
 
 
 
 
 
 
Table 6. On –study assessment 
Procedure 
(visit time window ± 3 days) 
C1D1 
 
C2D1 
 
≥C3D1 
Q 28 
days 
Notes 
Tumor Biopsy at first response 
evaluation 
 
 
 
 
 
Prior to C3 (or earlier if 
restaging performed early to 
Safety Assessment 
 
 
 
 
 
 
Vital Signs and 
Oxygen saturation 
X 
 
X 
 
X 
Temperature, BP, 
HR, RR, O2 saturation by 
pulse oximetry (also monitor 
amount 
of 
supplemental 
oxygen if applicable) prior to 
dosing and at any time a 
subject has any new or 
worsening 
respiratory 
symptoms 
Adverse 
Events 
(AE) 
Serious Adverse Events 
(SAE) Assessment 
X 
 
X 
 
X 
 
Physical Exam 
X 
 
X 
 
X 
Review 
of 
systems 
including measurements of 
weight, 
and 
ECOG 
Performance status 
Complete blood count 
(CBC) 
X 
 
X 
 
X 
Includes WBC count with 
differential, ANC, lymphocyte 
count, 
hemoglobin, 
hematocrit, and platelet count 
Serum Chemistry 
Tests 
X 
 
X 
 
X 
Serum chemistry 
(BUN or serum urea level, 
serum creatinine, sodium, 
potassium, 
calcium, 
magnesium, 
phosphate, 
chloride, and bicarbonate, 
glucose), LDH 
Liver Function Testing 
(Results obtained within 72 hours prior 
to dosing on utomilumab infusion days) 
X 
 
X 
 
X 
 


2017-0145 
March 20, 2018 
  
 
30 
 
 
 
 
 
Thyroid Function 
Testing 
X 
 
X 
 
X 
 
Whole blood for 
research and immunology studiesa 
X 
 
 
 
X 
C8D1and at PD, or 
C12D1 
Review of Concomitant 
Medications 
X 
 
X 
 
X 
Concomitant 
medications 
taken 
throughout the study 
duration should be 
recorded within the 
medical record. 
Pregnancy Test 
C1D1 and every 28 days 
Efficacy Assessments 
 
 
 
 
 
 
Radiographic 
Tumor 
Assessment b 
t 
 
 
 
 
X 
Every 8 weeks (± 7 
days)  
Clinical Drug Supplies 
 
 
 
 
 
 
Utomilumab 
X 
 
X 
 
X 
 
ISA101b vaccine 
X 
 
X 
 
X 
3 doses: C1D1, C2D1, 
C3D1 
a. Whole blood will be collected pre-treatment C1D1, pre-vaccination C2D1 and 
C3D1, pre-utomilumab C4D1 and C8D1, and at disease progression or study completion 
C12D1. 
 
bSubjects will be evaluated for response according to RECIST 1.1 and immune-related 
response criteria. 
 
Table 7. Follow-up and Survival Procedures 
 
Procedure 
Initial Follow-up 
phase: 
Follow-up #1 to occur 
30 days (±7 days) after 
last dose. follow-up #2 
to occur approximately 
70 days (±7 days) 
Further 
Follow-up 
Phase (beyond 
follow- up #2) 
Notes 
Radiographic 
 Tumor Assessmenta 
t 
X 
X 
For subjects who discontinue study treatment for 
reasons other than PD, follow up scans should 
be performed every 8 weeks (± 7 days) until PD, 
withdrawal of consent, death, lost to follow-up, or 
start of a subsequent anticancer therapy 


2017-0145 
March 20, 2018 
  
 
31 
 
 
 
 
 
Tumor Biopsy for response 
evaluation 
 
 
At progression (optional) 
Safety Assessment 
 
 
 
Vital Signs 
X 
X 
 
Physical Exam 
X 
X 
Review of systems including measurements 
of Weight, and ECOG Performance status 
Adverse 
Events 
(AE) 
and 
Serious 
Adverse Event (SAE) Assessment 
b
 
t 
X 
X 
 
 Complete blood count (CBC) 
X 
X 
Includes WBC count with differential, ANC, 
lymphocyte count, hemoglobin, hematocrit, 
and platelet count 
Serum Chemistry Tests 
X 
X 
Serum chemistry 
(BUN or serum urea level, serum creatinine, 
sodium, 
potassium, calcium, 
magnesium, 
phosphate, 
chloride, 
and 
bicarbonate, 
glucose), LDH 
Review 
of 
Concomitant 
Medications 
X 
 
 
Collection of 
Survival Informationc 
 
 
X 
X 
Direct contact (office visit) or phone 
call 
a. Radiographic assessments for subjects who have not experienced PD must be obtained every 8 
weeks (±7 days), and not delayed until follow-up #1 or #2. Patients with PD by RECIST 1.1 criteria 
at any point may be allowed to remain on study drugs unless they are demonstrating evidence of 
clinical progression. If the investigator feels the patient is benefiting and should continue on study, 
this should be documented in the medical record. 
b. Subjects will have two follow-up visits for safety within the first 100 days from the last dose 
of study therapy. Beyond 100 days from the last dose of study therapy, subjects will be 
followed for ongoing drug-related adverse events until resolved, return to baseline or 
deemed irreversible, or until lost to follow-up, withdrawal of study consent, or start of a 
subsequent anti-cancer therapy. 
c. All subjects will be followed for overall survival every 3 months until death, being lost to 
follow-up, or withdrawal of study consent, for up to 1.5 years (18 months). 
 
 
4.2 Efficacy Assessments 
 
4.2.1 Screening (Baseline visit) and On-Study Efficacy Assessments 
Study evaluations will take place in accordance with Table 5, and according to RECIST 1.1 
(Appendix 1). High resolution CT with PO/IV contrast or contrast-enhanced MRI are the 
preferred imaging modalities for assessing radiographic tumor response. If a subject has a 


2017-0145 
March 20, 2018 
  
 
32 
 
known allergy to contrast material, use local prophylaxis standards to obtain the assessment 
with contrast if at all possible, or use the alternate modality. In cases where contrast is strictly 
contraindicated, a non-contrast scan will suffice. All known or suspected sites of disease 
should be assessed at screening and at subsequent assessments using the same imaging 
method and technique. If more than one method is used at screening, then the most accurate 
method according to RECIST 1.1 should be used when recording data, and should again be 
used for all subsequent assessments. Bone scan, PET scan, or ultrasound are not adequate 
for assessment of RECIST response. In selected circumstances where such modalities are 
the sole modality used to assess certain non-target organs, those non- target organs may be 
evaluated less frequently. For example, bone scans may need to be repeated only when 
complete response is identified in target disease or when progression in bone is suspected. 
Subjects with a history of brain metastasis should have surveillance MRI approximately every 
12 weeks or as per local standard of care, or sooner if clinically indicated. Radiographic tumor 
assessments will be conducted at Week 8 (± 7 days) and every 8 weeks thereafter until 
disease progression (or until discontinuation of study therapy), lost to follow-up, withdrawal 
of study consent, or start of a subsequent anti-cancer therapy. Tumor assessments for all 
subjects should continue as per protocol even if dosing is interrupted. Tumor measurements 
should be made by the same investigator or radiologist for each assessment whenever 
possible. Changes in tumor measurements and tumor responses to guide ongoing study 
treatment decisions will be assessed by the investigator using RECIST 1.1 (see Appendix 1). 
 
4.2.2 Follow-up and Survival Procedures 
Subjects who discontinue study treatment prior to progression, and subjects being treated 
beyond disease progression, will be followed with radiographic tumor assessments every 8 
weeks (±7 days) until documented or further disease progression, withdrawal of  study 
consent, lost to follow-up, or beginning of a subsequent anti-cancer treatment. 
 
Radiographic assessments should be performed according to Section 4.1. 
Survival will be followed for up to 1.5 years after progression, either by direct contact (office 
visits) or via telephone contact, according to Table 7 until death, withdrawal of study consent, 
or lost to follow-up. 
 
4.2.3 Primary Efficacy Assessment 
This study has primary endpoint of ORR See section 6.5 for definitions of ORR. All subjects 
will be monitored by radiographic assessment on an every-8-week schedule [beginning from 
the first on-study assessment 8 weeks from start of treatment  (±7 days)] to determine 
changes in tumor size according to Section 4.2.1. RECIST 1.1 criteria will be used for the 
assessment (see Appendix 1). 
 
4.2.4 Secondary Efficacy Assessments 
For secondary efficacy analyses (response rate by irRC, RECIST PFS, Immune-related PFS, 
subjects will be monitored by radiographic assessment on an every-8-week schedule 
beginning from the first on-study assessment 8 weeks from start of treatment (±7days)], as for 
the primary efficacy assessment and according to Section 4.2.1. RECIST 1.1 and ir-Response 
criteria will be used for the assessment (see Appendix 1-2). Survival information will be 
collected as for the primary efficacy assessment. 
 
4.3 Other Assessments 
 
 
4.3.1 Biomarker Assessments 
Immune monitoring in tumor tissue and blood and tumor biopsies for the specimens from this 
trial may be supported by multiple sources, including, Industry sponsors (Pfizer, ISA), , HPV- 
Related Cancers Moonshot Flagship Project 3, and the MDACC Office of Clinical Research  


2017-0145 
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33 
 
 
Administration –sponsored Molecular Evaluation and /or Biopsy Related Support (MEBRS) 
program. 


2017-0145 
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34 
 
 
 
 
4.3.1.1 Peripheral Blood Markers 
Up to 150 mL (within 24 hours) of peripheral blood will be collected  for testing of 
biomarkers at the following time points: 
 
pre-vaccination C1D1, C2D1, and C3D1 
 
pre-utomilumab C4D1,  C8D1 
 
At disease progression or study completion (C12D1). 
 
The treating physician or designee will have the option to cancel the laboratory protocol 
collection for patient safety without protocol deviation. 
 
4.3.1.2 Tumor Markers 
 
 
Tumor tissue will be obtained at baseline, and as optional, and encouraged, procedures, prior 
to C3 (response evaluation), and at progression. 
Where possible PBMC and tumor biopsy samples pre- and post- treatment will be analyzed 
for expression of costimulatory and co- inhibitory ligands on tumor cells as well as the 
corresponding costimulatory / coinhibitory receptors, phenotypic differentiation and activation 
markers on effector cells and immune cell subset analysis using the panel of antibodies 
previously established by Dr. Wistuba in Translational Molecular Pathology and in the Curran 
Laboratory. 
 
 
PBMC and biopsy samples (if sufficient material is available) will be analyzed for at least 18 
paramaters including TCRb, CD8, CD4, FoxP3, CD127, CD11c, CD14, CD16, CD33, CD56, 
CD68, Ki67, HLA-DR, Eomesodermin, KLRG1, Granzyme B, PD-1, and HLA-A2 HPV E7 
Tetramer. Additional effort will be made to assess antigen specific responses from non-HLA- 
A2 patients, as well as to measure additional markers including Runx2, Granzyme K, CD45 
RO, CD62L, CD44, CD15, and fixable Live Dead. The goal is to assess the emergence of 
the ThEO phenotype (Eomesodermin+KLRG1+Granzyme B+) in CD4 and CD8 T cells as 
well as NK cells. Also, any influence of utomilumab on the balance of suppressive versus 
antigen-presenting myeloid cells will also be assessed. Biopsy samples will be studied by 
flow cytometry if sufficient material is available, otherwise they will be used for IHC (CD8, 
KI67, Granzyme B, CD4, FoxP3) or for gene expression analysis or HiSeq RNA sequencing. 
 
5.0 SAFETY MONITORING AND REPORTING 
 
 
5.1 ADVERSE EVENTS: Definitions and Reporting 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening 
of a pre-existing medical condition in a subject or clinical investigation subject administered 
an investigational (medicinal) product and that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of investigational product, whether or not considered related to the 
investigational product. 
 
The causal relationship to either or both study drugs is determined by a physician and should 
be used to assess all adverse events (AE). The casual relationship can be one of the 
following: 
Related: There is a reasonable causal relationship between study drug administration (either 
ISA101b, utomilumab or both) and the AE. 


2017-0145 
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35 
 
 
 
 
Not related: There is not a reasonable causal relationship between administration of either of 
the two study drugs (or both) and the AE. 
 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship to either or both investigational agents. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more AEs.) 
 
AEs will be reported using the NCI Adverse Events Reporting Guidelines below. 
 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
 
 
 
Phase II 
Phase II 
Phase II 
 
 
 
 
Phase III 
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
 
 
 
Phase II 
Phase II 
Phase II 
 
 
 
 
Phase III 
Phase III 
Possible 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
 
 
Phase III 
Phase III 
Phase III 
Phase III 
Probable 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
 
 
Phase III 
Phase III 
Phase III 
Phase III 
Definitive 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
  
Phase III 
Phase III 
Phase III 
Phase III  
 
 
5.1.1 Serious Adverse Events Reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
Death 
 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 


2017-0145 
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36 
 
 
 
 
 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21 CFR 312.32). 
 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
 
Appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional 
Review Board Policy for Investigators on Reporting Serious Unanticipated Adverse 
Events for Drugs and Devices”. Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IND Office, regardless of attribution 
(within 5 working days of knowledge of the event). 
 
All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office. 
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. 
 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the event has 
stabilized, or there has been acceptable resolution of the event. 
 
Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Potential drug induced liver injury (DILI) is also considered an important medical event. (See 
Section 5.5 for the definition of potential DILI.) 
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See 
Section 5.3 for reporting pregnancies). 
 
 
The following reasons for hospitalization or prolongation of existing hospitalization are not 
considered SAEs: 
 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed 
consent 
 
Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 
Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 


2017-0145 
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37 
 
 
 
 
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above is 
not a serious adverse event. 
 
 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, 
the protocol guidelines, the sponsor’s guidelines, and Institutional Review Board 
policy. 
 
5.1.2 Communication between Investigator and Pfizer and ISA 
If applicable, SAEs must be collected that relate to any protocol-specified procedure (e.g., a 
biopsy). An SAE report should be completed for any event where doubt exists regarding its 
status of seriousness. 
 
If the investigator believes that an SAE is not related to either study drug, but is potentially 
related to the conditions of  the study (such as withdrawal of previous therapy,  or a 
complication of a study procedure), the relationship should be specified in the narrative 
section of the SAE Report Form. 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to 
Pfizer and ISA within 24 hours. SAEs must be recorded on the SAE Report Form and for 
Pfizer, the Pfizer IIR SAE form and Reportable Event Fax Cover Sheer; pregnancies on a 
MD Anderson SAE Form and for Pfizer, the Exposure During Pregnancy supplemental 
form (electronic or paper forms). If the SAE is fatal or life-threatening transmission should 
occur immediately upon awareness. 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 72 hours to Pfizer and ISA 
using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should simultaneously be faxed to: 
Pfizer Inc 
Attention to Manali Talathi 
Fax: 1-866-997-8322Email: Manali.Talathi@pfizer.com 
ISA at: ISA Pharmaceuticals 
Attention to Sonja Visscher  Fax 
Number: +31 71 33 22 311 
Email: Visscher@isa-pharma.com. 
 
 
 
 
 
 
 
 


2017-0145 
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38 
 
 
 
 
5.2 Laboratory Test Abnormalities 
 
The following laboratory abnormalities should be captured: 
• Any laboratory test result that is clinically significant or meets the definition of an 
SAE 
• Any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
• Any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
 
It is expected that wherever possible, the clinical, rather than the laboratory term would 
be used by the reporting investigator (eg, anemia versus low hemoglobin value). 
 
 
5.3 Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (e.g., dose tapering if 
necessary for subject safety). 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. 
 
The investigator must immediately notify Pfizer and ISA of this event and complete and 
forward a MD Anderson SAE form to Pfizer and ISA within 72 hours and in accordance with 
SAE reporting procedures described in Section 5.1.2. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the MD Anderson 
SAE form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to Pfizer and ISA. Information on this pregnancy will be collected on the MD Anderson SAE 
Form. 
 
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 an SAE (see Section 5.1.1 for reporting details). 
 
 
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 (see Section 5.1.1. for reporting 
details). 
 
Potential drug induced liver injury is defined as 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 


2017-0145 
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39 
 
 
 
 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase), 
AND 
3) No other immediately apparent possible causes of AT 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. 
 
 
5.6 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, laboratory 
evaluations, electrocardiograms, x-rays, and any other potential safety assessments, 
whether or not these procedures are required by the protocol, should also be recorded as an 
AE or SAE, as appropriate, and reported accordingly. 
 
For recommendations regarding suspected pulmonary toxicity, diarrhea and colitis, 
suspected hepatotoxicity (including asymptomatic LFT 
elevations), or 
suspected 
endocrinopathy, please see Appendix 4: Management of Immune-Related Adverse Events. 
 
ISA101b, which includes the adjuvant Montanide, may be associated with ulceration of 
abscess formation up to 2 years after the last vaccination.  In addition, up to Grade 2 
systematic allergic reactions may be expected in approximately 7% of subjects receiving 
ISA101b. Please refer to the Investigator Brochure for ISA101-101b regarding additional 
information on safety and risk management. 
 
 
For the purpose of this study at MD Anderson Cancer Center, all patients will be registered 
in the Clinical Oncology Research System (CORE). All study related data will be captured in 
the Data Management Initiative (DMI). All adverse events, regardless of grade or attribution, 
will be documented in CORE. 
 
 
6.0 STATISTICAL CONSIDERATIONS 
 
6.1 Sample Size Determination 
 
A two-stage design will be used testing the null hypothesis that the true response rate is 0.10  
against a one-sided alternative of 30%. In the first stage, 15 evaluable patients will be 
accrued and response evaluated at week 8. If there are < 2 responses in these 15 patients, 
accrual  will be stopped and the trial closed for futility. Otherwise, 10 additional patients will 
be accrued for a total of 25 evaluable patients. The null hypothesis will be rejected if 6 or 
more responses are observed in 25 patients.  This design yields a type I error rate of 0.0328 
and power of .8017 when the true response rate is 30%. A response summary will be 
submitted to the IND Medical Monitor after the 15th subject and at the end of the trial.  
 
The Investigator is responsible for completing an Efficacy/Safety Summary Report, and 
submitting it to the IND Office Medical Affairs and Safety Group, for review and approval. This 
should be submitted after the first 5 evaluable patients, complete 8 weeks of study treatment, 
and every 5 evaluable patients thereafter. 
 
This design requires a maximum accrual of 27 patients, to provide 25 evaluable patients treated 
with utomilumab and ISA101b. 


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40 
 
 
 
 
6.2 Dose Limiting Toxicity (DLT) 
Toxicities will be graded according to CTCAE version 4.03. Toxicity must have possible, 
probable, or definite attribution to the study drugs. 
 
Table 1. Dose-Limiting Toxicity Definition 
 
 
 
Hematologic DLTs 
Grade 4 neutropenia (ANC <0.5 x 109/L) lasting >7 days 
Febrile neutropenia (defined as ANC <1.0 x 109/L and fever 
>38.5°C) or documented grade >3 infection with ANC <1.0 x 
109/L 
Platelet count <25,000/mm3 lasting > 7 days 
 
Grade 3-4 anemia 
Non-Hematologic 
DLTs 
 
 
Any grade 3-4 adverse event or grade 2 or greater ocular 
adverse event within 8 weeks of treatment. Grade 3 infusion 
reactions are exempt from the DLT definition. All grade 3 
immune- related adverse events that resolve to grade 1 or 
less within 28 days are exempt from the DLT definition 
excluding: pancreatitis, colitis, and ocular, hepatic and 
endocrine toxicities.  
Death  
Death occurring within 30 days of receiving the investigational 
agents considered at least possibly attributed to the agent(s) 
 
6.3 Stopping Rules for Toxicity 
DLT will be monitored continuously in cohorts of 5 patients for all 27 patients to ensure 
safety using the method by Thall et al (40). The trial will be stopped early for toxicity if 
Prob(DLT> 30%) > 0.90 using a prior of beta (0.6, 1.4). Stopping boundaries corresponding 
to this probability criterion are to terminate the trial if (# of patients with DLT) / (# patients 
evaluated) >= 4/5, 6/10, 8/15, 9/20, and 11/25. The operating characteristics of this rule 
follow: 
 


2017-0145 
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41 
 
 
P(true) 
P(stop) 
p10 
p25 
p50 
p75 
p90 
Avg # 
pts 
Avg # 
toxicities 
0.1 
0.0006 
27 
27 
27 
27 
27 
26.99 
2.70 
0.2 
0.0192 
27 
27 
27 
27 
27 
26.72 
5.35 
0.3 
0.1628 
20 
27 
27 
27 
27 
25.14 
7.54 
0.4 
0.5082 
10 
15 
25 
27 
27 
20.96 
8.40 
0.5 
0.8329 
5 
10 
15 
20 
27 
15.68 
7.83 
 
 
Accrual rate is estimated at 2 patients per month.  
 
Analysis plan: Summary statistics will be provided to summarize response, toxicity, and 
other categorical variables. Overall response rate by the RECIST 1.1 criteria will be 
estimated with 95% confidence interval. Progression free survival and overall survival will 
be summarized using the method of Kaplan and Meier and Cox proportional hazards 
model. 
 
Logistic regression and Cox proportional hazards models will be conducted to assess the value of 
peripheral and intra-tumoral ThEO/TcEo phenotype T cell formation on various clinical responses. 
Specifically, logistic regression models will be used to assess ORR 
 
 
and Cox models will be used for survival outcomes.  In both models, T cell formation will 
be our independent variable. 
 
 
 
6.4 Populations for Analyses 
 
All enrolled subjects: All subjects who signed an informed consent form and were 
registered. 
 
All treated subjects: All subjects who received at least one dose of ISA101b and/or 
one dose of utomilumab. This is the primary dataset for dosing and safety. 
 
Evaluable subjects: All subjects who receive at least one dose of ISA 101 and one 
dose of utomilumab and have had repeat imaging. 
 
Biomarker subjects: All treated subjects with pre-treatment tumor biopsy and 
blood biomarkers available 
 
 
6.5 Endpoint Definitions 
 
6.5.1 Primary Endpoint 
The primary objective in the study will be measured by ORR defined as the sum of subjects 
with a CR and PR divided by the number of evaluable subjects 8 wks from start of 
treatment. Response can be identified on any date between start of treatment and date of 
progression. For the purposes of determining response in the first 15 evaluable pts (per the 
mini-max design), only patients who have completed at least one restaging assessment 
will be included. If there are no responses at that time, accrual of new patients will be held 
while active patients are further followed and declared to be responding or progressing. 
 
-CR is defined as disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
-PR: is defined as at least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
-PD is defined as at least a 20% increase in the sum of 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 


2017-0145 
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42 
 
demonstrate an absolute increase of at least 5 mm. Note: the appearance of one or 
more new lesions is also considered progression. 
-SD is defined as neither sufficient shrinkage from the baseline study to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum diameters 
while on study. 
 
Best overall response (BOR) is defined as the best response designation, recorded between 
the date of start of treatment and the date of objectively documented progression per 
RECIST 1.1 (Appendix 1) or the date of subsequent anticancer therapy, whichever occurs 
first. For subjects without documented progression or subsequent anti-cancer therapy, all 
available response designations will contribute to the BOR determination. For subjects who 
continue utomilumab beyond progression, the BOR should be determined based on 
response designations recorded up to the time of the initial RECIST 1.1-defined progression. 
 
6.5.2 Secondary Endpoints 
 
 
The first secondary endpoint is safety and tolerability which will be measured by the 
incidence of adverse events, serious adverse events, deaths, and laboratory 
abnormalities. Adverse event assessments and laboratory tests are performed at 
baseline, and continuously throughout the study at the beginning of each 
subsequent cycle. 
 
The second secondary endpoints are clinical efficacy parameters other than 
RECIST-defined ORR and include: 
o immune-related ORR (ir-ORR) (ir CR + irPR) at 8 weeks from the start of 
treatment by the irRC (Appendix 2). ORR using the irRC is derived from 
time-point response assessments (based on tumor burden) as follows: 
- irCR, complete disappearance of all lesions (whether measurable or not, and no new 
lesions) with confirmation by a repeat, consecutive assessment no less than 4 wk from 
the date first documented 
- irPR, decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive 
assessment at least 4 weeks after first documentation 
- irSD, not meeting criteria for irCR or irPR, in absence of irPD 
-irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor 
burden) with confirmation by a repeat, consecutive assessment no less than 
4 wk from the date first documented. 
-Patients are considered to have irPR or irSD even if new lesions are present, as long as 
they meet the respective thresholds of response as described above. Furthermore, 
patients are not considered to have irPD if new lesions were present and the tumor 
burden of all lesions did not increase by ≥25%. In contrast to irCR, irPR, and irPD, a 
response of irSD does not require confirmation. Refer to Appendix 1 for more details 
about irRC. 
 
o PFS defined as the time from first day of treatment to the date of the first 
documented tumor progression (per RECIST 1.1), or death due to any cause. 
Subjects who die without a reported prior progression will be considered to have 
progressed on the date of their death. Subjects who did not progress or die will be 
censored on the date of their last evaluable tumor assessment. Subjects who did 
not have any on study tumor assessments and did not die will be censored on the 
date they were randomized. Subjects who started any subsequent anti- cancer 
therapy without a prior reported progression will be censored at the last evaluable 
tumor assessment prior to initiation of the subsequent anti-cancer therapy. 
 irPFS is defined as the time from treatment to the date of the first documented tumor 
progression (per irRC), or death due to any cause. 
OS is defined as the time from treatment to the date of death. 
 
The third secondary endpoint is HPV-specific immune response (Section 4.3.1). 


2017-0145 
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43 
 
 
6.5.3 Exploratory Endpoints 
Exploratory endpoints are other correlative markers of immune response 
(Section 4.3.1). 
 
 
6.5.4 Safety Analyses 
The safety analysis will be performed in all treated subjects. Descriptive statistics of safety 
will be presented using National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. All treatment emergent AEs, drug- related AEs, SAEs  
and drug-related SAEs will be tabulated using worst grade per NCI CTCAE v 4.03 criteria by 
system organ class and preferred term. 
 
On-study lab parameters including hematology, chemistry, liver function, thyroid function 
and renal function will be summarized using worst grade per NCI CTCAE v 4.03 criteria. 
Toxicity will be monitored continuously in cohorts of 5patients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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44 
 
 
7.0 References: 
 
1. 
Ferris RL, Blumenschein G, Fayette J, Guigay J, Colevas AD, Licitra L, et al. 
NIvolumab for recurrent squamous-cell carcinoma of the head and neck. New Engl J 
Med . 2016;375:1856-67.  
2. 
Bauml J, Seiwert TY, Pfister DG, Worden F, et al. Pembrolizumab for platinum- and 
cetuximab-refractory head and neck cancer: Results from a single-arm phase II study. 
J Clin Oncol 2017;35: 1542-49. 
3. 
Glisson B, Massarelli E, William W, Johnson F, Kies M, Ferrarotta R et al. Nivolumab 
and ISA101 vaccine in patients with incurable HPV-16+ cancer.  2017 ESMO 
Congress,  Abstract 11360. 
4. 
Sabbagh L, Pulle G, Liu Y, Tsitsikov EN, Watts TH. ERK-Dependent Bim Modulation 
Downstream of the 4-1BB-TRAF1 Signaling Axis Is a Critical Mediator of CD8 T Cell 
Survival In Vivo. The Journal of Immunology. 2008;180:8093-101. 
5. 
Croft M. The role of TNF superfamily members in T-cell function and diseases. Nat Rev 
Immunol. 2009;9:271-85. 
6. 
Lynch DH. The promise of 4-1BB (CD137)-mediated immunomodulation and 
the immunotherapy of cancer. Immunological Reviews. 2008;222:277-86. 
7. 
Vinay D, Cha K, Kwon B. Dual immunoregulatory pathways of 4-1BB signaling. J Mol 
Med. 2006;84:726-36. 
8. 
Segal NH, Gopal AK, Bhatia S, Kohrt HE, Levy R, Pishvaian MJ, et al. A phase 1 
study of PF- 05082566 (anti-4-1BB) in patients with advanced cancer. J Clin Oncol. 
2014;32:3007abstract. 
9. 
Gopal AK, Bartlett NL, Levy R, Houot R, Smith SD, Segal NH, et al. A phase I study of 
PF- 05082566 (anti-4-1BB) + rituximab in patients with CD20+ NHL. J Clin Oncol. 
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11. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J 
Med. 2009;361:1838-47. 
12. Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, 
et al. Phase I immunotherapeutic trial with long peptides spanning the E6 and E7 
sequences of high-risk human papillomavirus 16 in end-stage cervical cancer patients 
shows low toxicity and robust immunogenicity. Clinical cancer research : an official 
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blockade expands infiltrating T cells and reduces regulatory T and myeloid cells 
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19. Bartkowiak T, Singh S, Yang G, Galvan G, Haria D, Ai M, et al. Unique potential of 4-
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the United States of America. 2015;112:E5290-9. 
20. Pfizer. Investigator's Brochure PF-05082566. Sept 2014. 
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APPENDIX 1 
 
 
RECIST 1.1 CRITERIA 
This Appendix has been excerpted from the full RECIST 1.1 criteria. For information 
pertaining to RECIST 1.1 criteria not contained in the study protocol or in this Appendix, 
please refer to the full publication (1) 
 
 
1 ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 
Measurable disease is defined by the presence of at least one measurable lesion. 
 
 
1.1 Measurability of tumor 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non- 
measurable as follows.  All baseline evaluations should be performed as close as possible 
to the treatment start and never more than 4 weeks before the beginning of the treatment. 
Measurable lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of the measurement to be recorded) with a minimum size of: 
• 10 mm by CT scan - (CT scan slice thickness no greater than 5 mm) 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
• 20 mm by chest x-ray 
• 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. 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. 
Special considerations regarding lesion measurability 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence 
or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such 
as CT or MRI can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic lesions: 
• 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. 


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However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
Non-measurable lesions are all other lesions, including small lesions (longest diameter 
< 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as non- 
measurable lesions. 
Lesions considered non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques. 
 
1.2 Method of assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. Imaging 
based evaluation should always be performed rather than clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical examination. CT, 
MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice  thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. 
Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than x-ray, particularly in identifying new 
lesions. However, lesions on chest x-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers. For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may be 
reviewed at the end of the study. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. 
 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
 
 
2 BASELINE DOCUMENTATION OF ‘TARGET’ AND 
‘NONTARGET’ LESIONS 
Target lesions: When more than one measurable lesion is present at baseline all lesions 
up to a maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and will be 
recorded and measured at baseline. 


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Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, and should lend 
themselves to reproducible repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. Pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥15 mm by CT scan. Only the short axis of these nodes will contribute to the 
baseline sum. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should not be considered non-target lesions. Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 
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. The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease) including pathological lymph 
nodes should be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as ‘present’, 
‘absent’, or ‘unequivocal progression’.  In addition, it is possible to record multiple non- 
target lesions involving the same organ as a single item on the case record form (e.g., 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
 
3 TUMOR RESPONSE EVALUATION AND RESPONSE CRITERIA 
 
 
3.1 Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial 
Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of 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 progression. 
Stable Disease (SD): Neither sufficient shrinkage from the baseline study to qualify for 
PR nor sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
 
Special notes on the assessment of target lesions 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded and should be measured in the same anatomical plane 
as the baseline examination, even if the nodes regress to below 10 mm on study. This 
means that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not 
be zero even if complete response criteria are met, since a normal lymph node is defined 
as having a short axis of <10 mm. 
• Target lesions that become ‘too small to measure’: All lesions (nodal and nonnodal) 
recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). If the radiologist is able to provide an actual 
measure, that should be recorded, even if it is below 5 mm. 


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However, when such a lesion becomes difficult to assign an exact measure to 
then: (i) if it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
(ii) if the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned (note: in case of a lymph node believed to be 
present and faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well). This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness). 
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to 
calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them 
may be maintained that would aid in obtaining maximal diameter measurements of 
each individual lesion. If the lesions have coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 
 
 
3.2 Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be 
measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: 
the appearance of one or more new lesions is also considered progression). 
• The concept of progression of non-target disease requires additional explanation as 
follows: 
• When the patient also has measurable disease: To achieve ‘unequivocal progression’ 
on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. 
• When the patient has only non-measurable disease: To achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening such that the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non- target 
lesions is usually not sufficient to qualify for unequivocal progression status. Because 
worsening in non-target disease cannot be easily quantified (by definition: if all lesions are 
non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on 
the change in non-measurable disease is comparable in magnitude to the increase that 
would be required to declare PD for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase 
diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as 


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‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point. 
 
 
3.3 New lesions 
The appearance of new malignant lesions denotes disease progression. The finding of a 
new lesion should be unequivocal: i.e., not attributable to differences in scanning technique, 
change in imaging modality or findings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or flare of pre- existing lesions). 
This is particularly important when the patient’s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as 
a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of 
this is the patient who has visceral disease at baseline and while on study has a CT or MRI 
brain ordered which reveals metastases. The patient’s brain metastases are considered to 
constitute PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents new disease. If repeat scans confirm that 
there is a new lesion, then progression should be declared using the date of the initial scan. 
 
 
3.4 Tumor markers 
Tumor markers alone cannot be used to assess objective tumor responses.  If markers 
are initially above the upper normal limit, however, they must normalize in order for a 
patient to be considered as having attained a complete response. 
 
 
4 EVALUATION OF BEST OVERALL RESPONSE 
 
 
4.1 Time point response 
A response assessment should occur at each time point specified in the protocol. 
For patients who have measurable disease at baseline Table 1 provides a summary of the 
overall response status calculation at each time point 
 
Appendix Table 1. Summary of the Overall Response Status Calculation [Time 
point response: patients with target (+/-) non-target disease] 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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4.2 Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at 
an assessment, usually the case is also considered NE at that time point, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned time point response. This would be most likely to happen 
in the case of PD. 
 
 
4.3 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that patients with CR may not have a total sum of ‘zero’ on the case 
report form (CRF). 
Patients 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 objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy. The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Appendix Table 1. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date 
of progression should be the earlier date when progression was suspected. 
 
 
5 ADDITIONAL CONSIDERATIONS 
 
 
5.1 Duration of response 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are first met for CR/PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded on study). 
The duration of overall complete response is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment 
(in randomized trials, from date of start of treatment) until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, 
this is the reference for calculation of PD). 
 
 
5.2 Lesions that disappear and reappear 
If a lesion disappears and reappears at a subsequent time point it should continue to be 
measured. However, the patient’s response at the point in time when the lesion reappears 
will depend upon the status of his/her other lesions. For example, if the 


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patient’s tumour had reached a CR status and the lesion reappeared, then the patient 
would be considered PD at the time of reappearance. In contrast, if the tumour status was 
a PR or SD and one lesion which had disappeared then reappears, its maximal diameter 
should be added to the sum of the remaining lesions for a calculated response: in other 
words, the reappearance of an apparently ‘disappeared’ single lesion amongst many which 
remain is not in itself enough to qualify for PD: that requires the sum of all lesions to meet 
the PD criteria. The rationale for such a categorization is based upon the realization that 
most lesions do not actually ‘disappear’ but are not visualized because they are beyond 
the resolving power of the imaging modality employed. 
 
 
5.3 Use of FDG-PET 
While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. Confirmatory CT is recommended. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
• If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is progression occurring at 
that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
 
 
Reference: 
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. (2009); 45:228- 
247. 


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APPENDIX 2 
 
 
Immune-related Response Criteria (irRC) 
 
 
Antitumor response based on total measurable tumor burden 
 
For the irRC, only index and measurable new lesions are taken into account (in contrast 
to conventional WHO criteria, which do not require the measurement of new lesions, nor 
do they include new lesion measurements in the characterization of evolving tumor 
burden). At the baseline tumor assessment, the sum of the products of the two largest 
perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral 
lesions and five cutaneous index lesions) is calculated. At each subsequent tumor 
assessment, the SPD of the index lesions and of new, measurable lesions (≥5 × 5 mm; up 
to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) are added 
together to provide the total tumor burden: 
 
 
 
 
 
Appendix Table 2. Comparison between WHO criteria and the irRC 
 
WHO 
irRC 
New, measurable 
lesions (i.e., ≥5 × 5 
mm) 
 
Always represent PD 
 
Incorporated 
into 
tumor 
burden 
New, 
nonmeasurable 
lesions (i.e., <5 × 5 
mm) 
 
 
Always represent PD 
 
Do not define progression (but 
preclude irCR) 
 
Non-index lesions 
 
Changes contribute to defining BOR 
of CR, PR, SD, and PD 
Contribute to defining irCR 
(complete disappearance 
required) 
 
CR 
Disappearance of all lesions in two 
consecutive observations not less 
than 
Disappearance of all lesions in 
two consecutive observations 
not less than 4 wk apart 
 
 
 
PR 
≥50% decrease in SPD of all index 
lesions compared with baseline in two 
observations at least 4 wk apart, in 
absence 
of 
new 
lesions 
or 
unequivocal progression of non-index 
lesions 
 
≥50% 
decrease 
in 
tumor 
burden compared with baseline 
in two observations at least 4 
wk apart 
SD 
50% decrease in SPD compared with 50% decrease in tumor burden 


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55 
 
 
 
WHO 
irRC 
 
baseline cannot be established nor 
25% increase compared with nadir, in 
absence 
of 
new 
lesions 
or 
unequivocal progression of non-index 
lesions 
compared with baseline cannot 
be 
established 
nor 
25% 
increase compared with nadir 
 
 
 
PD 
At least 25% increase in SPD 
compared 
with 
nadir 
and/or 
unequivocal progression of non-index 
lesions and/or appearance of new 
lesions (at any single time point) 
At least 25% increase in tumor 
burden compared with nadir (at 
any single time point) in two 
consecutive observations at 
least 4 wk apart 
 
Time-point response assessment using irRC 
 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear. At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the 
change in tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed 
relative to baseline measurements (i.e., the SPD of all index lesions at screening). The irRC 
were derived from WHO criteria and, therefore, the thresholds of response remain the same 
(Appendix Table 3). However, the irRC response categories have been modified from those 
of WHO criteria as detailed in Tables 2 and 3. 
 
Table 3. Derivation of irRC overall responses 
 
Measurable response 
 
Nonmeasurable response 
Overall 
respons 
Index and new, measurable 
lesions (tumor burden),* % 
 
Non-index 
lesions
New, nonmeasurable
lesions 
 
Using irRC 
↓100 
Absent 
Absent 
irCR† 
↓100 
Stable 
Any 
irPR† 
 
↓100 
Unequivocal 
progression 
 
Any 
irPR† 
↓≥50 
Absent/Stable 
Any 
irPR† 
 
↓≥50 
Unequivocal 
progression 
 
Any 
irPR† 
↓<50 to <25↑ 
Absent/Stable 
Any 
irSD 
 
↓<50 to <25↑ 
Unequivocal 
progression 
 
Any 
 
irSD 
≥25? 
Any 
Any 
 
irP † 
D
 
*Decreases assessed relative to baseline, including measurable lesions only (>5 × 
5 mm). 
† Assuming response (irCR) and progression (irPD) are confirmed by a second, 
consecutive assessment at least 4 weeks apart. 


2017-0145 
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56 
 
Overall response using the irRC 
The overall response according to the irRC is derived from time-point response assessments 
(based on tumor burden) as follows: 
 
irCR, complete disappearance of all lesions (whether measurable or not, and no new 
lesions) 
 
o confirmation by a repeat, consecutive assessment no less than 4 wk from the 
date first documented 
 
irPR, decrease in tumor burden ≥50% relative to baseline 
 
o confirmed by a   consecutive  assessment at   least  4   wk 
after first 
documentation 
 
irSD, not meeting criteria for irCR or irPR, in absence of irPD 
 
irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor 
burden) 
 
o confirmation by a repeat, consecutive assessment no less than 4 wk from the 
date first documented 
 
Patients were considered to have irPR or irSD even if new lesions were present, as long as 
they met the respective thresholds of response as described above. Furthermore, patients were 
not considered to have irPD if new lesions were present and the tumor burden of all lesions 
did not increase by ≥25%. In contrast to irCR, irPR, and irPD, a response of irSD does not 
require confirmation. It is important to note that irCR, irPR, and irSD include all patients with 
CR, PR, or SD by WHO criteria as well as those patients that shift to these irRC categories 
from WHO PD. Patients with irSD, particularly those with slow-declining tumor burden ≥25% from 
baseline at the last tumor assessment, are considered clinically meaningful because they show 
an objectively measurable reduction in tumor burden without reaching the 50% threshold that 
defines irPR (it represented an objectively measured reduction not commonly observed in 
the natural history of advanced melanoma patients). 
 
If a patient is classified as having irPD at a post-baseline tumor assessment, then confirmation 
of irPD by a second scan in the absence of rapid clinical deterioration is required. The 
definition of confirmation of progression represents an increase in tumor burden ≥25% 
compared with the nadir at two consecutive time points at least 4 weeks apart. It is 
recommended that this be done at the discretion of the investigator because follow- up with 
observation alone may not be appropriate for patients with a rapid decline in performance 
status. Confirmation of irPD allows for the capture of all observed responses using the irRC 
(Table 2), as most of these late-responding patients have a trend toward response within 4 
weeks after initial irPD. Whereas WHO criteria consider any new measurable lesion to indicate 
PD, determination of immune-related best overall response (irBOR) is based on changes in 
total tumor burden from the baseline (nadir, for irPD) tumor assessment, regardless of any 
initial increase in baseline lesions or the appearance of new lesions. 


2017-0145 
 
 
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57 
 
Appendix 3 Immune- Related Adverse Event Management Algorithms 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and 
appropriately treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive 
diagnostic or therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 
 
 
 
Appendix Table 4. Management of Immune-Related Adverse Events 
Gastrointestinal irAEs 
Diarrhea / Colitis 
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Diarrhea: <4 stools/day over 
baseline; 
Colitis: asymptomatic 
Continue investigational product 
therapy 
Symptomatic treatment (eg, 
loperamide) 
Close monitoring for worsening 
symptoms 
Educate patient to report worsening 
immediately 
If worsens: 
Treat as Grade 2 or 3/4 
Grade 2 
Diarrhea: 4 to 6 stools per day 
over baseline; IV fluids indicated 
<24 hours; not interfering with 
ADL 
Colitis: abdominal pain; blood in 
stool 
Delay investigational product 
therapy 
Symptomatic treatment 
If improves to Grade 1: Resume 
investigational product therapy 
If persists >5-7 days or recur: 
0.5 
to 
1.0 
mg/kg/day 
methylprednisolone 
or 
equivalent 
When symptoms improve to Grade 1, 
taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume 
investigational product therapy per 
protocol. 
If worsens or persists >3 to 5 days 
with oral steroids: 
Treat as Grade 3 to 4 


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58 
 
 
Grade 3 to 4 
Diarrhea (Grade 3): ≥7 stools per 
day over baseline; incontinence; 
IV fluids ≥24 hrs; interfering with 
ADL 
Colitis (Grade 3): severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs 
Grade 4:Life-threatening perf. 
Discontinue investigational product 
therapy per protocol 
1.0 to 2.0 mg/kg/day 
methlyprednisolone IV or 
equivalent 
Add prophylactic antibiotics for 
opportunistic 
infections 
Consider lower endoscopy 
If improves: 
Continue steroids until Grade 1, then 
taper over at least 1 month 
If persists >3 to 5 days, or recur after 
improvement: 
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab 
should not be used in cases of 
perforation or sepsis 
 
Dermatological irAEs 
Rash 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 to 2 
Covering ≤ 30% body surface area 
Symptomatic 
therapy 
(eg, 
antihistamines, topical steroids) 
Continue investigational product 
therapy 
If persists >1 to 2 weeks or recurs: 
Consider skin biopsy 
Delay 
investigational 
product 
therapy 
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone 
IV 
or 
oral 
equivalent. Once improving, taper 
steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic 
infections, 
and 
resume 
investigational 
product 
therapy 
If worsens: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Covering >30% body surface area; 
life threatening consequences 
Delay 
or 
discontinue 
investigational product therapy 
Consider 
skin 
biopsy 
Dermatology consult 
1.0 
to 
2.0 
mg/kg/day 
methylprednisolone 
IV 
or 
IV 
equivalent 
If improves to Grade 1: 
Taper steroids over at least 1 month 
and add prophylactic antibiotics for 
opportunistic infections 
Resume investigational product 
therapy 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Radiographic changes only 
Consider delay of investigational 
product therapy 
Monitor for symptoms every 2 to 
3 days 
Consider 
Pulmonary 
and 
Infectious Disease consults 
Re-image at least every 3 
weeks If worsens: 
Treat as Grade 2 or Grade 3 to 4 


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59 
 
 
Grade 2 
Mild to moderate new symptoms 
Delay 
investigational 
product 
therapy 
Pulmonary 
and 
Infectious 
Disease consults 
Monitor symptoms daily, 
consider hospitalization 
1.0 mg/kg/day 
methyl-prednisolone IV or oral 
equivalent 
Consider 
bronchoscopy, 
lung 
biopsy 
Re-image every 1 to 3 days 
If improves: 
When symptoms return to near 
baseline, taper steroids over at 
least 1 month and then resume 
investigational product therapy and 
consider prophylactic antibiotics 
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Severe new symptoms; New / 
worsening hypoxia; life-threatening 
Discontinue investigational 
product 
therapy 
Hospitalize 
Pulmonary and Infectious 
Disease consults 
2 to 4 mg/kg/day 
methylprednisolone 
IV 
or 
IV 
equivalent 
Add prophylactic antibiotics for 
opportunistic 
infections 
Consider bronchoscopy, lung 
biopsy 
If improves to baseline: 
Taper steroids over at least 6 
weeks If not improving after 48 
hours or worsening: 
Add additional immunosuppression 
(eg, infliximab, cyclophosphamide, 
intravenous 
immunoglobulin, 
or 
mycophenolate mofetil) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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60 
 
Hepatic irAEs 
Liver Function Tests (LFT) Increase 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Grade 1 AST or ALT > ULN to 
3.0 x ULN and/or Total bilirubin 
> ULN to 1.5 x ULN 
Continue investigational product 
therapy 
Continue liver function monitoring If 
worsens: 
Treat as Grade 2 or 3 to 4 
Grade 2 
AST or ALT >3.0 to ≤5 x ULN 
and/or total bilirubin >1.5 to 
≤3 x ULN 
Delay 
investigational 
product 
therapy 
Increase frequency of monitoring 
to every 3 days 
If returns to baseline: Resume 
routine monitoring, 
resume investigational product therapy 
If elevations persist >5 to 7 days or 
worsen : 
0.5 to 1 mg/kg/day methylprednisolone 
or oral equivalent and when LFT returns 
to Grade 1 or baseline, taper steroids 
over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume investigational 
product therapy 
Grade 3 to 4 
 
AST or ALT >5 x ULN and /or total 
bilirubin >3 x ULN 
 
Management 
Discontinue 
investigational 
product therapy 
Increase frequency of monitoring 
to every 1 to 2 days 1.0 to 2.0 
mg/kg/day 
methylprednisolone 
IV or IV equivalent.  
Add prophylactic antibiotics for 
opportunistic infections. 
Consult gastroenterologist 
Consider obtaining MRI/CT scan 
of liver and liver biopsy if 
clinically warranted 
Follow-up 
If returns to grade 2 Taper 
steroids over min. 1 mo 
If no improvement >3-5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gm 
twice daily 
If 
no 
response 
within 
an 
additional3-5 
days 
consider 
other immunosuppressants per 
local guidelines 


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61 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endocrine irAEs 
Endocrine Disorder 
Management 
Follow-up 
Asymptomatic TSH abnormality 
Continue investigational product therapy 
If TSH <0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 2 
subsequent measurements: include free T4 at subsequent cycles as 
clinically indicated; consider endocrinology consult 
Symptomatic endocrinopathy 
Evaluate endocrine function 
Consider 
pituitary 
scan 
Symptomatic with abnormal 
lab / pituitary scan: 
Delay investigational 
product therapy 
1 to 2 mg/kg/day 
methylprednisolone IV or by 
mouth equivalent 
Initiate appropriate hormone 
therapy 
No abnormal lab / pituitary 
MRI scan but symptoms 
persist: 
Repeat labs in 1 to 3 weeks / 
MRI in 1 month 
If improves (with or without hormone 
replacement): 
Taper steroids over at least 1 month 
and consider prophylactic antibiotics 
for opportunistic infections 
Resume investigational product 
therapy 
Patients with adrenal insufficiency 
may need to continue steroids with 
mineralocorticoid component 
Suspicion of adrenal crisis (eg, 
severe dehydration, hypotension, 
shock out of proportion to current 
illness) 
Delay or discontinue investigational product therapy 
Rule out sepsis 
Stress dose of IV steroids with mineralocorticoid activity 
IV fluids 
Consult endocrinologist 
If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathy 
ADL=activities of daily living, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 


2017-0145 
 
 
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62 
 
irAE=immune-related AE=immune-related adverse event, IV=intravenous, LLN=lower limit of normal, MRI=magnetic 
resonance imaging, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events, 
NSAIDs=nonsteroidal anti-inflammatory drugs, T4=thyroxine, TSH=thyroid-stimulating hormone, ULN=upper limit of 
normal