A Phase II Study of Type-1 Polarized Dendritic Cell (aDC1) -Based Treatment in Combination With Tumor-Selective Chemokine Modulation (CKM: Interferon Alpha 2b, Rintatolimod and Celecoxib) in Melanoma Patients With Primary PD-1/PD-L1 Resistance
Phase: PHASE2
Conditions: HLA-A2 Positive Cells Present, Refractory Melanoma
Sponsor: Roswell Park Cancer Institute

Document Coversheet 
 Study Title: 
A Phase II Study of Type-1 Polarized Dendritic Cell (αDC1) based Treatment in Combination with Tumor-
Selective Chemokine Modulation (CKM: Interferon alpha 2b, Rintatolimod and Celecoxib) in Melanoma 
Patients with Primary PD-1/PD-L1 Resistance 
Institution/Site: 
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
08/11/2025 
NCT Number: 
NCT04093323 
IRB Number 
I 82419 

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PROTOCOL TITLE:
A Phase II Study of Type-1 Polarized Dendritic Cell (αDC1) -based Treatment in 
Combination with Tumor-Selective Chemokine Modulation (CKM: Interferon alpha-2b, 
Rintatolimod and Celecoxib) in Melanoma Patients with Primary PD-1/PD-L1 Resistance
PROTOCOL NUMBER:
I 82419
PRINCIPAL INVESTIGATOR
Igor Puzanov, M.D., M.S.C.I., F.A.C.P.
Roswell Park Comprehensive Cancer Center
Elm and Carlton Street
Buffalo, New York 14263
716-845-2300, x7505
Igor.Puzanov@RoswellPark.org
VERSION NUMBER:
6
DATE:
August 11, 2025
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party(ies) mentioned above (Roswell Park Cancer Institute 
Corporation d/b/a Roswell Park Comprehensive Cancer Center). The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party(ies) above.
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CO- INVESTIGATORS: Scientific
Pawel Kalinski, MD, PhD
Professor, Department of Obstetrics, Gynecology & Reproductive Sciences
University of Pittsburgh School of Medicine
Vice Chair of Translational Research Development in Women’s Health
Magee-Women’s Research Institute
204 Craft Avenue, Suite B411, Pittsburgh, PA15213
Telephone: (412) 641-8555 
Email: KalinskiP2@upmc.edu
Walter J. Storkus, PhD
Professor of Dermatology
W1151 BST
200 Lothrop Street
Pittsburgh, PA 15213
Phone: (412)-648-9981 
Fax: (412)-383-5857
storkuswj@upmc.edu
BIOSTATISTICIAN
Han Yu, PhD Roswell Park Comprehensive Cancer Center
Elm and Carlton Street
Buffalo, New York 14263
716-845-5389
Han.Yu@RoswellPark.org 
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Table of Contents
1
Objectives ................................................................................................................................4
2
Background..............................................................................................................................4
3
Inclusion and Exclusion Criteria .............................................................................................7
4
Local and Study-Wide Number of Subjects ............................................................................9
5
Local and Study-Wide Recruitment Methods .......................................................................10
6
Multi-Site Research ...............................................................................................................10
7
Study Timelines.....................................................................................................................10
8
Study Endpoints.....................................................................................................................10
9
Design....................................................................................................................................11
10
Treatment...............................................................................................................................13
11
Procedures Involved ..............................................................................................................20
12
Withdrawal of Subjects..........................................................................................................22
13
Risks to Subjects....................................................................................................................23
14
Potential Benefits to Subjects ................................................................................................24
15
Data and Specimen Banking..................................................................................................24
16
Measurement of Effect ..........................................................................................................24
17
Safety Evaluation...................................................................................................................26
18
Data Management and Confidentiality..................................................................................31
19
Statistical Plan .......................................................................................................................32
20
Provisions to Monitor the Data to Ensure the Safety of Subjects..........................................34
21
Vulnerable Populations..........................................................................................................34
22
Community-Based Participatory Research............................................................................35
23
Sharing of Results with Subjects ...........................................................................................35
24
Setting....................................................................................................................................35
25
Provisions to Protect the Privacy Interests of Subjects .........................................................35
26
Resources Available ..............................................................................................................35
27
Prior Approvals......................................................................................................................36
28
Compensation for Research-Related Injury...........................................................................36
29
Economic Burden to Subjects................................................................................................36
30
Consent Process.....................................................................................................................36
31
Process to Document Consent in Writing..............................................................................37
32
Drugs or Devices ...................................................................................................................37
33
References..............................................................................................................................43
34
Appendices ............................................................................................................................46
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1
OBJECTIVES
1.1
Primary Objective

To evaluate the objective response rate to treatment with an autologous αDC1/TBVA cell-
based treatment (alpha-type-1-polarized dendritic cells loaded with tumor blood vessel-
targeting antigenic peptides) plus cytokine modulating (CKM) regimen (rintatolimod, IFN-
α2b and, celecoxib) in HLA-A2+ subjects with primary PD-1 resistant IO-refractory 
melanoma (who will continue the original PD-1/PD-L1-regimen for 12 weeks).
1.2
Secondary Objectives*

To evaluate the immune-related objective response rate (ORR; per iRECIST;) in the above 
patient population treated with autologous αDC1/TBVA cell-based treatment plus cytokine 
CKM regimen followed by continued treatment with PD-1/PD-L1 blockade (± CTLA4 
blockade or LAG3 blockade)

Evaluate rate of durable responses (> 6 months) on the combination treatment in the above 
patient population treated with autologous αDC1/TBVA cell-based treatment plus cytokine 
CKM regimen followed by continued treatment with PD-1/PD-L1 blockade (± CTLA4 
blockade or LAG3 blockade)
* Note: The secondary objectives are in reference to patients that continue on with either PD-1/PD-
L1 and/or CTLA4 blockade after meeting the 12-week primary objective. 
1.3
Exploratory Objective

Examine whether the combination of peptide-loaded autologous αDC1 cell-based 
treatment and tumor-selective chemokine modulation (CKM:  IFN-a2b, rintatolimod, and 
celecoxib) improves the OS and iPFS in HLA-A2+ subjects PD-1/PD-L1-refractory 
melanoma compared to the historical control of the best supportive care.

Identify the intratumoral and systemic immune correlates of the response to treatment
2
BACKGROUND
The incidence of melanoma continues to rise, with the American Cancer Society estimating that 
over 91,000 patients will be diagnosed with this form of cancer in 2018, with an estimated death 
toll of over 9,320 (1). Despite recent therapeutic successes for immune checkpoint blockade in the 
setting of advanced-stage disease, only a minority of treated melanoma patients manifest durable 
benefit (2-5), reinforcing the need to develop 2nd-line therapies that are effective against 
checkpoint-refractory disease. Results from our recently completed phase II clinical trial UPCI 12-
048 (“A Randomized Phase II Pilot Study of Type I-Polarized Autologous Dendritic Cell Vaccines 
Incorporating Tumor Blood Vessel Antigen (TBVA)-Derived Peptides in Combination with 
Dasatinib in Patients with Metastatic Melanoma”(6), suggests a link between patient objective 
clinical response and their ability to develop: i) a pro-inflammatory CK-dominated tumor 
microenvironment 
(i.e. 
increased 
expression 
of 
pro-inflammatory 
CKs 
CCL5/CCL19/CCL21/CXCL10 and reduced expression of regulatory CKs CCL22/CXCL12); ii) 
peripheral Type-1 CD8+ T cell responses against vaccine-incorporated antigens (as well as TBVA 
and melanoma antigens not in the vaccine formulation; i.e. as an index of “epitope spreading”), 
iii) increased TCR convergence (focus on specific MHC/peptide complexes) and the presence of 
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unique TIL clonotypes not detectable in peripheral blood (TCRseq) and, iv) a biomarker signature 
for tertiary lymphoid structures (TLS) within their tumors (including the canonical TLS-associated 
CKs CCL19, CCL21) 5 weeks after the initiation of therapy, and in advance of spreading in the 
CD8+ T cell repertoire or CT-documented objective clinical response (OCR; RECIST). Overall, 
objective clinical benefit was observed in 6 of 13 (46%) evaluable patients, including 4/7 
(57%) patients exhibiting prior primary resistance to PD1 blockade. Importantly for the 
primary endpoint of this study, all of the objective clinical responses were observed already 
within 9 weeks of DC1/TBVA treatment of PD1-non-responsive patients. New preliminary 
data developed in mouse melanoma models supports the superior anti-tumor efficacy of 
αDC1/TBVA vaccines in HLA-A2 Tg mice when combined with the CKM regimen vs. dasatinib, 
prompting the performance of our proposed innovative clinical trial.
2.1
Pre-Clinical Studies
Intratumoral density of effector T cells (CD8+ CTLs) in melanoma tissue predicts patients’ 
responsiveness to PD-1/PD-L1 blockade, and overall clinical outcomes (7-17). Our preclinical 
data show that melanoma antigen-loaded alpha-type-1-polarized dendritic cells (αDC1s) induce 
highly effective melanoma-specific CD8+ CTLs that express chemokine receptors CCR5 and 
CXCR3. We also observed that the treatment of melanoma or other cancer tissues with interferon-
alpha (IFNα) combined with a TLR3 ligand synergistically enhances local production of the 
relevant chemokines able to attract CCR5- and CXCR3-expressing CTLs (CXCL10/IP10 and 
CCL5/RANTES) selectively in the tumor lesions, rather than in marginal healthy tissues, while 
simultaneously suppressing local production of chemokines that attract undesirable Treg cells 
(CCL22). Our completed phase I of clinical trial NCT01545141 in patients with advanced 
colorectal cancer demonstrated that the chemokine modulatory combination (CKM) involving  
one-to two five-day-long cycles of (IFNα) (Intron-A, up to 20MU/M2; i. v.) with rintatolimod 
(Ampligen, short half-life selective TLR3 ligand formulated for i. v. use; 200 mg) and celecoxib 
(Celebrex, selective COX2 blocker, 2 x 200 mg; p.o.) is safe and is capable of significantly 
enhancing the ratios between CTL-attractants versus Treg attractants in patients’ tumor tissues. 
Our additional experience within phase I/II trial NCT02151448 (four cycles of CKM combined 
with αDC1 vaccine loaded with autologous tumor material) further demonstrated very good 
tolerability of this combination treatment (unpublished data from University of Pittsburgh 
collaborators).
We and others have also shown that dendritic cell (DC) vaccines targeting antigens that are 
selectively (over)expressed by tumor associated vascular endothelial cells (VEC) or pericytes 
(TBVA: DLK1, EphA2, HBB, NRP1, RGS5 and TEM) (12), are both safe and effective against 
established murine tumors,(10, 15, 16) including B16 and BP (BRAFV600EPTEN-/-) melanomas. 
Importantly, we failed to detect, (i.) vaccine-induced T cell reactivity against normal tissue 
pericytes or VEC, (ii.) delay in the kinetics of skin closure after full thickness wounding or, (iii.) 
alterations in the pregnancy or litter sizes of female mice vaccinated against TBVA (16, 18).
2.2
Clinical Studies
Based on the results developed in HLA-A2 Tg (HHD) mice, the FDA approved the translation of 
this dendritic cell-based treatment approach in a first-in-human phase II clinical trial (UPCI 12-
048; NCT01876212) of an autologous alpha-DC1/TBVA peptide-based cell therapy (coordinately 
targeting 6 TBVA: DLK1, EphA2, HBB, NRP1, RGS5 and TEM) (19) for the treatment of 
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advanced-stage melanoma; observing their safety and ability to induce radiologic responses in 
patients with advanced melanomas who previously progressed on checkpoint blockade. 
Importantly, in the subset of patients with primary PD-1-reistance (7/13 patients), the objective 
response rate (ORR) was 57% (4 of 7 patients) providing a strong rationale to evaluate the ability 
of αDC1/TBVA to reverse the primary PD1 resistance.
2.3
Rationale
Our preliminary translational and clinical (UPCI 12-048/NCT01876212) data support the ability 
of treatment consisting of αDC1/TBVA + agents to augment pro-inflammatory CKs (and reduce 
regulatory CKs) in the TME to improve therapeutic TIL recruitment/function and yield OCR in 
melanoma patients exhibiting prior primary checkpoint resistance. Although we observed a 57% 
response rate to αDC1/TBVA vaccination + dasatinib-based immunotherapy in UPCI 12-048, our 
translational modeling suggests that treatment with a combination vaccine + CKM regimen may 
yield greater therapeutic efficacy based on more robust changes in CK profiles in the TME, 
including augmented expression of CCL5, CCL19, CCL21, CXCL10 and CXCL13 (associated 
with naïve/effector T cell recruitment and TLS formation) and reduced expression of regulatory 
cell-recruiting CKs CCL22 and CXCL12 (Figure 1)
Figure 1. αDC1/TBVA vaccines exhibit greater anti-tumor efficacy when combined with CKM vs. dasatinib. HLA-
A2 Tg mice bearing established day 10 subcutaneous (SC). B16 melanomas (right flank) were left untreated or they 
were treated by SC injection (left flank) with 5 x 105 syngeneic bone marrow-derived αDC1 loaded with TBVA 
peptides (VAC; identical to those used in UPCI 12-048/NCT01876212) on days 7, 14 and 21 ± i.p. dasatinib (DAS; 
0.1 mg/mouse) or CKM [rintatolimod (50 µg), rmIFNα (10,000U), celecoxib (75 µg)]. Tumor cell growth was 
monitored every 3-4 days (A), with harvested tumor biopsies analyzed by qRT-PCR (B) for the indicated analytes on 
day 25 (n = 5 mice/group); *p < 0.05 for vaccine/CKM vs. vaccine/DAS on days > 13.
Our group has already demonstrated (NCT01545141, NCT02151448) that the CKM regimen 
(involving 1-2 five-day-long cycles of (IFNα) (Intron-A, up to 20 MU/M2; i. v.) with rintatolimod 
(Ampligen, short half-life selective TLR3 ligand formulated for i. v. use; 200 mg) and celecoxib 
(Celebrex, selective COX2 blocker, 2 x 200 mg; p.o.) is both safe and capable of significantly 
enhancing the ratio between CTL-attractants (inflammatory CKs) versus Treg attractants 
(regulatory CKs) in patients’ tumor tissues. In the case of NCT02151448, CKM treatment was 
combined with an αDC1-base vaccine (i.e. DC loaded with autologous tumor material) and found 
to exhibit very good tolerability.
-200
0
200
400
800
1000
VAC
VAC/DAS
VAC/CKM
10
15
20
25
0
100
200
300
400
Untreated
VAC
VAC/DAS
VAC/CKM
B16 Size (mm2) 
Days Post Tumor Inoculation
A
B
Fold Increase in Tumor Transcript
Expression  vs. Untreated Control
*
CCL5
CXCL10
CCL19
CCL21
CXCL13
LTA
CCL22
CXCL12
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In view of these preliminary data, we hypothesize that the treatment of PD-1/PD-L1-refractory 
melanoma patients with the combination of αDC1 vaccines loaded with DLK1, EphA2, HBB, 
NRP1, RGS5 and TEM peptides, and CKM (to enhance the entry of cytotoxic T-lymphocytes into 
melanoma lesions) will promote both systemic immunization and robust infiltration of 
vaccination-induced CD8+ CTLs to tumor lesions, and, subsequently, tumor regression with 
improved patient survival.
Rationale for using Bioferon as a component of CKM. While the original protocol involved 
INTRON-A (Merck-produced IFN2b), as a component of the CKM regimen (in addition to 
rintatolimod and celecoxib), Merck’s decision to discontinue the production of INTRON®-A, 
forced us to identify an alternative IFNa2b to perform the trial and revise the original BB-
IND16,704. We have recently identified (Bioferon®, from Argentinian supplied by Biosidus 
S.A.), as a IFNα2b product used at the same 20 MU/M2 dose as the INTRON®-A dose used in the 
trial conducted under BB-IND16,704. Bioferon® is not FDA-approved and is considered an 
investigational new drug in the United States. For safety reason, in analogy to the recently 
approved ND 163681 (also held by Roswell Park and FDA-approved on October 14, 2022), which 
covers the same CKM + PD-1/PD-L1 blockade regimen but without a DC vaccine component, we 
propose an additional lead-in phase I cohort of 3 patients to be treated with reduced-dose CKM 
including Bioferon at a dose of 10 MU/m2. Following the testing of lower dose of IFNα2b in these 
3 initial patients, and in the absence of dose-limiting adverse effects, we will continue the accrual 
of patients to be treated using a Bioferon dose of 20MU/m2. We will retain the original protocol 
design but consider safety as the formal primary endpoint for these additional 3 patients. The data 
from these patients will be shared between the lead-in and phase II component for overall treatment 
efficacy evaluations.  
The use of Bioferon to replace INTRON A, was FDA approved on October 14, 2022 (IND 163681 
- held by Roswell Park). The revision of BB-IND16,704 includes a letter of cross-reference to IND 
163681.
3
INCLUSION AND EXCLUSION CRITERIA
This Phase II trial will be applicable to HLA-A2+ subjects with primary PD-1/PD-L1 resistant IO-
refractory melanoma with normal organ and marrow function.
3.1
Inclusion Criteria
To be included in this study, participants must meet the following criteria:
1. Age ≥ 18 years of age.
2. Participant must be HLA-A2+. Retesting is not required for patients who have previous 
documented positivity.
3. Have IO-refractory melanoma with primary PD-1/PD-L1-resistance. Note: Any lines of 
prior therapies are allowed, but the last line needs to include an anti PD-1 or anti PD-
L1 agent. The prior treatments may include any standard and/or experimental therapies.
4. Have > 1 tumor site amenable to core needle biopsy that is not the site of disease used to 
measure antitumor response
5. Have measurable disease based on RECIST 1.1 criteria present,
6. Have an ECOG Performance Status of 0-2. Refer to Appendix A.
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7. Have normal organ and marrow function as defined below:
o
Platelets ≥ 75,000/ microliter
o
Hemoglobin ≥ 9 g/ deciliter
o
Absolute Neutrophil Count (ANC) ≥ 1500/microliter
o
Creatinine < 1.5 X institutional upper limit of normal (ULN) OR creatinine 
clearance ≥ 50 mL/min by Cockroft-Gault formula for subjects with creatinine 
levels ≥ 1.5 x ULN (Appendix D).
o
Total bilirubin not greater than 1.5 X institutional ULN, except for patients with 
known Gilberts Syndrome, who are eligible to no more than 2 X institutional ULN.
o
AST(SGOT) and ALT(SGPT) no greater than 3 x institutional ULN OR, no greater 
than 5 x ULN for subjects with liver metastases
8. Participants of child-bearing potential must agree to use adequate contraceptive methods 
(e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should 
a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.
9. Participant must understand the investigational nature of this study and sign an Independent 
Ethics Committee/Institutional Review Board approved written informed consent form 
prior to receiving any study related procedure.
10. Candidate for continuation/resumption of anti-PD-1/PD-L1 blockade (in parallel to DC 
vaccine and CKM).
Refer to Appendix B for the Investigator Study Eligibility Verification Form: Inclusion Criteria.
3.2
Exclusion Criteria
Participants will be excluded from this study for the following:
1. Is currently being treated with systemic immunosuppressive agents, including steroids: 
Subjects will be ineligible until 3 weeks after removal from immunosuppressive 
treatments, except when they are administered as replacement therapy for endocrine 
dysfunction (and receive no more than 10 mg prednisone or equivalent: inhaled steroids 
are allowed).
2. Has had prior anti-cancer therapy within 2 weeks prior to study day 1 or who has not 
recovered (i.e., no more than Grade 1 or at baseline) from adverse events due to a 
previously administered agent, except for neuropathy (no more than Grade 2) or alopecia 
or vitiligo (any grade).
3. Has a known additional malignancy that is progressing or requires active treatment.
4. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Treated brain metastases are allowed, if stable for more than 4 weeks (and 
receive no more than 10 mg prednisone or equivalent: inhaled steroids are allowed).
5. Has a history of cardiac event(s) (acute coronary syndrome, myocardial infarction, or 
ischemia (within 3 months of signing consent) or, subject has a New York Heart 
Association classification of III or IV (Appendix E).
6. Has an active infection requiring systemic therapy.
7. Has known active Hepatitis B or Hepatitis C infection.
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8. Has known immunosuppressive disease (e.g. HIV, AIDS or other immune depressing 
disease). Testing is not mandatory.
9. Has known serious hypersensitivity reactions to peg-interferon alpha-2b or interferon 
alpha-2b.
10. Prior allergic reaction or hypersensitivity to sulfonamides, celecoxib, or NSAIDs.
11. Has received a blood transfusion in the two weeks prior to leukapheresis.
12. Women of childbearing potential who are pregnant or nursing.
13. Unwilling or unable to follow protocol requirements.
14. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate or unacceptable risk to receive study drug regimen.
15. Patients who showed initial response to PD-1/PD-L1 blockade and developed secondary 
resistance.
Refer to Appendix C for the Investigator Study Eligibility Verification Form: Exclusion Criteria.
3.3
Special Populations
The following special populations will be excluded from this study:

Cognitively impaired adults/adults with impaired decision-making capacity

Individuals who are not yet adults (infants, children, teenagers)

Pregnant women

Prisoners
3.4
Inclusion of Women and Minorities
The integrated clinical trial is open to patients of any sex, race, or ethnic background. Based on 
the SEER Database, the incidence of melanoma is greater in males versus females and in 
Caucasians versus minorities. We expect to enroll minorities proportional to their representation 
in the Buffalo, NY regional population.
No patients will be excluded based on sex, race, or ethnic origin. An attempt to increase enrollment 
of women and minorities will be made by promoting the clinical trial through several unique 
Roswell Park programs designed to reach out to women and minorities, increase their awareness 
of clinical trial, and help support them should they choose to participate in clinical research 
protocols.
3.5
Inclusion of Children
Only subjects over 18 years of age will be included in the clinical protocol. Melanoma is rare in 
children under 18 years of age, and we do not expect to see a child under 18 who is qualified for 
inclusion. We would work in collaboration with our pediatric oncology colleagues should this 
occur.
4
LOCAL AND STUDY-WIDE NUMBER OF SUBJECTS
A maximum of 24 evaluable participants at Roswell Park will be enrolled (8 participants per year 
over a period of 3 years).
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5
LOCAL AND STUDY-WIDE RECRUITMENT METHODS
Participants will be identified/recruited/screened from patients at the Melanoma Clinic at Roswell 
Park, referring physicians and, from multi-disciplinary conference discussion.  Patients will also 
be recruited through The Roswell Park Care Network sites.
Roswell Park Care Network patients will be given the option to complete an internal HIPAA 
Authorization form. If obtained, this authorization will allow Roswell Park study teams to access 
patient medical records for review of potential eligibility for clinical trials. In addition, this 
authorization includes an agreement to be contacted by Roswell Park. Patients who have a signed 
authorization on file will have records reviewed for eligibility for this trial. Roswell Park staff 
will work with primary oncologist at Roswell Park Care Network to approach patients and 
patients will be presented with study information by approved study team members. The Roswell 
Park Care Network sites will not be engaged in research and all research activities will be carried 
out at Roswell Park Main Campus.
6
MULTI-SITE RESEARCH
Not applicable: This is a single-site study.
7
STUDY TIMELINES
Subjects will be on active experimental treatment for 12 weeks, with continued PD-1/PD-L1 
blockade. In the absence of disease progression, patients will continue PD-1/PD-L1 blockade as 
per SoC and be followed for PFS and OS within routine care. 
Patients with progressive disease at 12 weeks can at the physician’s discretion, begin LAG-3 or 
CTLA-4 ± PD-1/PD-L1 inhibitor treatment and will be followed as per standard of care for this 
disease group.
Patients will continue to be monitored for PFS and OS within standard care visits (every 3 months 
for up to 2 years).
8
STUDY ENDPOINTS
8.1
Primary Endpoint

Objective response rate (ORR) at 12 weeks (only in participants who have completed the 
first 3 treatment cycles) will be evaluated using RECIST 1.1criteria.
8.2
Secondary Endpoints

Objective response rate (ORR) at 6 months (using iRECIST criteria)(20)

Durable objective response rate (DORR ≥ 6 months): to be calculated from the time of first 
confirmed response 
8.3
Exploratory/ Correlative Studies 

Immune-related progression-free survival (PFS; using iRECIST criteria)

Overall Survival (OS)
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
Changes in the density of CD8+ CTLs and molecular biomarkers (OmniSeq immune report 
card, IRC) in paired tumor tissues collected at pre- and post-treatment (changes in the 
molecular markers and magnitude and character of immune infiltrate may be evaluated in 
paired tumor tissues collected at pre- and post-treatment, using additional methods, 
depending on the availability of funding).
9
DESIGN
This is a single-arm Phase II study with a 3 patient safety lead-in cohort to evaluate the clinical 
efficacy and immunomodulatory action of a combination treatment regimen consisting of a type-
1 polarized dendritic cell (DC1)-based therapy and tumor-selective chemokine modulation 
(CKM: interferon alpha-2b, rintatolimod and celecoxib) in HLA-A2+ subjects with PD-1/PD-L1-
refractory advanced-stage melanoma, who will continue the original SoC (PD-1/PDL-1 blockade). 
The study schema is depicted in Figure 2.
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Figure 2
Study Schema
Advanced stage IO-refractory melanoma 
with PD-1/PD-L1 resistance
Pre-screening for HLA-A*02
Enrollment (the original PD-1/PD-L1 
regimen will continue until week 12)
Leukapheresis 
Biopsy
Study Treatment Regimen
•
Cycle 1 Days 1-3 (week 1): CKM regimen only
•
Cycles 2-4 Days 1-3 (week 4, 7, 10):
αDC1 αDC1 cell-based injection* + CKM regimen
*note: The αDC1 cell-based injection is administered only on Day 1 of 
Cycles 2-4 (1 hr +30 min/ -15 min) prior to initiating CKM pre-treatment)
**note: original PD-1/PD-L1 treatment regimen will be given as per 
standard of are ordered by the provider
Biopsy (week 11)
Disease Assessment 
(Week 12 CT scan)
SOC PD-1/PD-L1 inhibitor or best 
alternative care
LAG-3 or CTLA-4 ± PD-1/PD-L1 
inhibitor
PD
CR, PR, SD
SOC follow-up every 3 mos for up to 2 years
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Figure 3
*Patients will continue the original PD-1/PD-L1 blockade as Standard of Care upon entering the 
study and will continue until the 12-week decision point shown in Figure 2, when a switch to a 
combination ICB (with CTLA4 or LAG3 blocker) can be made in case of PD.
This is a single-arm Phase II study with a safety lead-in cohort, to evaluate the anti-tumor efficacy 
of combined αDC1/TBVA vaccination (Vx) + CKM in primary PD-1/PD-L1-refractory melanoma 
patients. DC cellular treatment will be produced by the Therapeutic Cell Production Shared 
Resource (TCP) at Roswell Park. OCR will be determined by PET/CT imaging after CKM cycle 
4. Tumor biopsies (2 per patient), PBMC & serum (> 7 per patient; pre-/post-therapy) will be 
collected at for immunologic/molecular analysis. Follow-up treatment (post week 12) will be 
based on patient objective complete response (OCR) status.
At week 12, response will be evaluated by CT scan, performed as a part of standard care. Any 
patient with PD will be offered an opportunity to switch to PD-1/PD-L1 inhibitor combined with 
either CTLA4 blockade (Ipilimumab) or with LAG3 blockade, unless contra-indicated, and will 
be assessed as per standard of care guidelines. Any patient with a CR, PR or SD will be offered 
PD-1/PD-L1 blockade (according to the approved standard of care regimen) or best alternative 
care. Thereafter patients will be contacted by phone every 3 months for up to 2 years by medical 
record review/telephone call for survival status and other anti-cancer therapies.
10 TREATMENT
After CT/PET imaging confirmation of PD-1/PD-L1-resistance status, patients will be screened 
for HLA-A2+ status (using flow cytometry) and, for all relevant inclusion/exclusion criteria.
A patient apheresis will be performed to isolate peripheral blood monocytes to generate the 
autologous αDC1/TBVA cell-based treatment.
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In each of 4 cycles of combination immunotherapy, enrolled subjects will receive a three-day-long 
course (days 1-3) of CKM (IFN alpha-2b [20 MU/m2 i. v. over 30 min], rintatolimod [200 mg i. 
v. over 2.5 h] and celecoxib [200 mg p.o. 30 min (can be up  to 2 hours earlier) before IFN alpha-2b 
and 200 mg p.o. 12 hrs after IFN alpha-2b; 8-16 hours are acceptable)]). In addition, on day 1 only 
of cycles 2-4, subjects will receive the αDC1 cell-based treatment (10 million cells intradermal) 
prior to the chemokine modulating regimen. 
On days of the αDC1 injection, patients will be monitored as outpatients (approximately every 
20 minutes) for 1 hour after the injection Pre-treatment prior to the CKM regimen will begin 1 hr 
(± 10 min) following the αDC1 injection. Additionally, at approximately 1 hr (± 10 min) after the 
administration of the αDC1 cell-based treatment, vital signs will be obtained and assessment of 
the injection sites will be documented).
Treatment is intended for an outpatient setting. 
Due to the need to replace INTRON-A (as originally proposed for use) with Bioferon, as we have 
recently done for FDA-approved IND 163681 which covers the same CKM + PD-1/PD-L1 
blockade regimen but without a DC vaccine component, we propose inclusion of an additional 
lead-in phase I cohort of 3 patients to be treated with a reduced-dose CKM employing Bioferon at 
an initial dose of 10 MU/m2. Following testing of this lower dose of IFNα2b in 3 patients, and in 
the absence of any dose-limiting adverse effects, we will continue the accrual patients to be treated 
at a Bioferon dose of 20MU/m2. We will retain the original protocol design but will consider safety 
as the formal primary endpoint for these initial 3 patients to be included in the phase II efficacy 
evaluations.  
10.1 Dosing and Administration
10.1.1 Chemokine Modulating (CKM) Regimen
The chemokine modulating regimen will be administered on an outpatient basis at Roswell Park 
over 3 consecutive days (days 1-3) for 4 treatment cycles (1 cycle = 21 days).
On each CKM dosing day, the patient will be given the following medications in the following 
order:

Pre-treatment: 500 mL Normal saline IV over 60 minutes

Pre-meds: Acetaminophen (Tylenol) 650 mg by mouth x 1 dose; Prochlorperazine 
(Compazine) 10 mg by mouth x 1 dose – administered 30 minutes (±5 minutes) after 
starting pre-treatment hydration. The CKM treatment will begin 30 minutes (±5 minutes) 
after that, at completion of IV normal saline

Celecoxib: 200 mg orally, administered along with pre-meds (2 hrs to 30 min prior to 
interferon alpha-2b)

Interferon Alpha-2b: (20 million units/M2, with the exception of the initial 3 patients who 
will receive a (reduced) dose of 10 MU/m2) IV over 30 minutes 

Rintatolimod: 200 mg IV, initial administration should begin at a slow rate of infusion 
(approximately 20 cc/ hour) and increase to 40 cc/ hour after 30 minutes (15-45 mins range 
is acceptable). Tubing should be flushed with 30 to 50 mL of normal saline solution upon 
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completion. Administration will be followed by 1 hour of observation with vital signs at 
30 and 60 minutes post infusion (± 5 minutes)

Post-CKM Regimen:
o
Celecoxib: The patient will be instructed to take the second dose of celecoxib 
(200 mg orally) at home, approximately 12 hours following the initial dose of 
celecoxib.
Pre-treatment normal saline and pre-meds listed above are recommendations and may be modified 
based upon institutional SOC requirements and at the discretion of the investigator.
10.1.2 αDC1/TBVA Cellular Therapy
Dendritic cells (DC) are derived from autologous adherent mononuclear cells in the peripheral 
blood by 5-day or 6- day culture in the presence of interleukin 4 (IL-4) and granulocyte-
macrophage colony stimulating factor (GM-CSF), followed by an additional period of antigen 
loading and maturation. To generate the autologous DC-based cellular treatment, patients will 
undergo a 90 minute leukapheresis to obtain an enriched population of monocytes as a precursor 
source for DC developed in culture.
Leukapheresis
Outpatient leukapheresis will be performed in the Therapeutic Apheresis unit. Antecubital veins 
will be used, or when necessary, a central catheter will be placed. A standard collection protocol 
will be used to obtain the peripheral white blood cells with settings modified according to the 
COBE Spectra Apheresis System recommendations to obtain the best mononuclear cell yield. In 
order to obtain sufficient monocytes cells, leukapheresis time may vary from 90 minutes to 
240 minutes. Approximately 10 L to 15 L of blood will be circulated by leukapheresis in order to 
retrieve approximately 500 x 106 blood monocytes. The cell yield from a leukapheresis procedure 
is variable. Autologous leukapheresis product, counts, and recoveries will be monitored for each 
donation. The procedure will be performed according to leukapheresis SOPs at Roswell Park. The 
leukapheresis product will be transported to the cGMP Therapeutic Cell Production Facility by a 
designated staff member of the cGMP Therapeutic Cell Production Facility. Before moving the 
product from the collection area, the donor center staff and the designee will confirm the following 
information: Patient’s Name, Medical Record Number, and Date/Time of Collection. If the 
labeling is incomplete it must be corrected before the product leaves the collection area. Monocytes 
will be cultured as described below. Other leukapheresis fractions will be used in the Immune 
Analysis Facility to assess immunologic parameters.
The cell yield from a leukapheresis procedure is variable. However, it is expected that 1 
leukapheresis will yield enough cells for the 3 intradermal αDC1/TBVA injections. If a sufficient 
number of cells have not been obtained, an additional leukapheresis may be required in order to 
complete the treatment protocol. The second leukapheresis will be performed within 14 days of 
the first. If a sufficient number of cells for 3 intradermal αDC1/TBVA injections and proposed QC 
testing are still not obtained after the second leukapheresis, the patient will be withdrawn from the 
study.
Preparation of Dendritic Cells
The αDC1/TBVA cells will be generated in the cGMP Therapeutic Cell Production Shared 
Resource of Roswell Park under the Roswell Park-held FDA-approved BB-IND-16,704 with 
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qualified SOPs for generation, cryopreservation, and preparation for administration of the 
αDC1/TBVA cell-based treatment. The cGMP Facility staff will follow SOPs, perform Quality 
Control (QC) and Quality Assurance (QA) procedures and manage associated documentation 
pertaining to products manufactured for clinical trials in this facility. Qualified personnel who are 
familiar with the procedures, which minimize undue exposure to them and to the environment, 
will undertake the preparation, handling, and safe disposal of immunotherapeutic agents in a self-
contained protective environment
Intradermal αDC1 Vaccination Administration
Treatment will be administered on an outpatient basis. When the patient is ready for the 
administration of the intradermal αDC1 cell treatment, the required dose (in a single tuberculin 
syringe with attached new 27 gauge safety-glide needle and suspended in 5% albumin) will be 
hand-carried by a designee to the patient area. The product will be transported on ice in sealed 
sterile plastic bag in a small “igloo”-type cooler. Prior to releasing the αDC1 cellular product from 
the cGMP Therapeutic Cell Production Shared Resource, the following information will be 
verified: Patient Identification Number (PIN) and Medical Record Number (MR#). Prior to 
injection, the same information will again be verified. Each 0.2 mL of the αDC1 cell suspension 
will contain approximately 10 x 106 cells and will be loaded onto a single tuberculin syringe. The 
αDC1 cell suspension will be administered intradermally (i. d.) by the investigator or qualified 
designee. The investigator/designee will inject approximately 0.1 mL of the syringe contents 
intradermally and then will remove the needle from the patient. Using the same needle, the 
investigator/designee will then inject the remaining 0.1 mL of the syringe contents intradermally 
on the opposite side of the body (the other thigh). The upper thighs are the preferred locations for 
the injections, however upper arms are also allowed. The injections will be administered within 
6 hours of thawing and release (target: 2 hrs).
Patients will be monitored (every 20 min± 5 min) as outpatients for 1 hour after αDC1 cell 
injection. Monitoring will consist of vital sign measurements, and monitoring of any 
local/systemic reactions to the injection. This monitoring will include clinical assessment of pain, 
tenderness, warmth and swelling. Appropriate laboratory tests will be performed based on the 
judgment of the clinical investigators if clinical side effects are apparent.
10.2 Dose Modifications and Treatment Delays
The following dose modification rules will be used with respect to potential toxicity. Toxicity will 
be assessed according to the NCI Common Terminology Criteria for Adverse Events Version 5.0 
(CTCAE v5.0). The initial 3 patients will receive a reduced dose of IFN2b (10MU/m2), to obtain 
initial safety confirmation for the new source of IFN2b. In the absence of dose-limiting adverse 
effects, we will proceed to use the full dose IFN2b (20MU/M2) in the CKM regimen. In case of 
dose limiting toxicities, we will suspend accrual and consult the DSMC for the development of 
extended safety plan and protocol revision.
In case of observation of toxicities in the initial 3 patients, in additional patients we may suspend 
the PD-1/PD-L1 blockade for the 12 week duration of the experimental treatment and resume it 
(alone or combined with either CTLA4- or LAG3 blockade) at week 12.
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10.2.1 Celecoxib Hematologic and Non-Hematologic Toxicities
Considered to be possibly, probably, or definitely related to Celecoxib (Interferon Alpha-2b and 
rintatolimod will be continued). Celecoxib will be discontinued for any grade ≥ 3 toxicity 
attributed to Celecoxib.
10.2.2 Interferon alpha-2b and/or rintatolimod Hematologic and Non-hematologic 
toxicities
Considered to be possibly, probably, or definitely related to Interferon Alpha-2b and rintatolimod:
Interferon alpha-2b

Hematologic Toxicities:
For grade 3 toxicity:
o
If < 7 days to resolution (transfusion are allowed): Treatment to continue if toxicity 
is resolved to ≤ grade 1 or baseline) at a dose reduction of 33%. The dose can be 
re-escalated if toxicity remains at ≤ grade 1 or baseline.
o
If > 7 days to resolution: Treatment to continue if toxicity is resolved to ≤ grade 1 
or baseline at the next study visit at a dose reduction of 33%. The dose cannot be 
re-escalated.
o
2nd incidence:  Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline 
at the next study visit at a dose reduction of 33%. (total 66% reduction if the dose 
was not re-escalated). The dose cannot be re-escalated.
For Grade 4 toxicity:
o
If < 7 days to resolution (transfusions are allowed): Treatment to continue if toxicity 
is resolved to ≤ grade 1 or baseline at the next study visit at a dose reduction of 
33%. The dose cannot be re-escalated.
o
If > 7 days to resolution: Discontinue

Non-Hematologic toxicities
For grade 3 toxicity:
o
1st episode: Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline) 
at a dose reduction of 33%. The dose can be re-escalated if toxicity remains at ≤ 
grade 1 or baseline.
o
2nd episode: Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline 
at the next study visit at a dose reduction of 33%. (a total of 66% reduction if the 
dose was not re-escalated). The dose cannot be re-escalated.
For grade 4 toxicity:
o
1st episode: Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline at 
the next study visit at a dose reduction of 33%. The dose cannot be re-escalated.
o
2nd episode: Off study, patient will be followed until the event resolves to ≤ grade 
1 or baseline study (patient may receive pembrolizumab off of the protocol at 
treating physician’s discretion)
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Rintatolimod

Hematologic Toxicities:
For grade 3 toxicity:
o
If < 7 days to resolution (transfusion are allowed): Treatment to continue if toxicity 
is resolved to ≤ grade 1 or baseline) at a dose reduction of 33%. The dose can be 
re-escalated if toxicity remains at ≤ grade 1 or baseline.
o
If > 7 days to resolution: Treatment to continue if toxicity is resolved to ≤ grade 1 
or baseline at the next study visit at a dose reduction of 33%. The dose cannot be 
re-escalated.
o
2nd incidence: Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline 
at the next study visit at a dose reduction of 33%. (a total of 66% reduction if the 
dose was not re-escalated). The dose cannot be re-escalated.
For Grade 4 toxicity:
o
If < 7 days to resolution (transfusions are allowed): Treatment to continue if toxicity 
is resolved to ≤ grade 1 or baseline at the next study visit at a dose reduction of 
33%. The dose cannot be re-escalated.
o
If > 7 days to resolution: Discontinue

Non-Hematologic toxicities:
For grade 3 toxicity:
o
1st episode: Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline) 
at a dose reduction of 20%. The dose can be re-escalated if toxicity remains at ≤ 
grade 1 or baseline.
o
2nd episode: Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline) 
at a dose reduction of 20% (total dose reduction 20% if dose was not re-escalated). 
The dose can be re-escalated if toxicity remains at ≤ grade 1 or baseline.
For grade 4 toxicity:
o
1st episode: Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline) 
at a dose reduction of 20% (total dose reduction 20% if dose was not re-escalated). 
The dose can be re-escalated if toxicity remains at ≤ grade 1 or baseline.
o
2nd episode: Off study (patient may receive pembrolizumab off of the protocol at 
treating physician’s discretion)
10.2.3 Toxicity Management
The toxicity of high dose interferon (20 million units/ m²/d) has been established by Kirkwood et 
al in a number of trials. Most notable was the E1684 trial (21) where HDI (20 million units/m²/d) 
was administered daily for 5 days x 4weeks. In that trial (n=143), grade 3 toxicities were 67%, 
grade 4 toxicities were 9% (mainly constitutional and neurologic), and there were 2 treatment 
related mortalities (grade 5) due to hepatoxicity. The proportion of Grade 3 and 4 toxicities in that 
trial were 48.2% for constitutional toxicities (defined as ‘worst grade of any constitutional toxicity, 
including fever, chills, flu-like symptoms, fatigue, malaise, and diaphoresis), and 66% for non-
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constitutional toxicities (23.8% for myelosuppression, 13.9% for hepatotoxicity, 28% for 
neurological toxicity).
These are suggestions for specific toxicities and may be modified for institutional guidelines and 
treating physician preference.
Gastrointestinal Toxicity:

Nausea and/or vomiting should be controlled with adequate antiemetic therapy. 
Prophylactic antiemetic therapy can be used at the discretion of the investigator/sub-
investigator. Subjects are encouraged to take plenty of oral fluids.

Diarrhea should be managed with appropriate antidiarrheal therapy. Subjects should be 
encouraged to take plenty of oral fluids. If symptoms do not decrease to grade 1 or less 
with adequate antidiarrheal therapy, all protocol drugs should be held until resolved to < 
grade 1.
Pain/Fever/Chills

For chills and/or fever or mild local pain, acetaminophen will be utilized at the discretion 
of the investigator/sub-investigator or designee.
Hypersensitivity Reactions
Caution: Subjects who had a mild to moderate hypersensitivity reaction have been successfully re-
challenged, but careful attention to prophylaxis and bedside monitoring of vital signs is 
recommended. Hypersensitivity reactions to Interferon Alpha-2b and/or rintatolimod will be 
managed as follows:

Mild symptoms (e.g., mild flushing, rash, pruritus): Complete infusion. Supervise at 
bedside. No treatment required.

Moderate symptoms (e.g., moderate rash, flushing, mild dyspnea, chest discomfort): Stop 
infusion. Give intravenous diphenhydramine 50 mg and intravenous famotidine 20 mg. 
Resume infusion after recovery of symptoms at a 66% slower rate, then, if no further 
symptoms, rate can be titrated up every 5-10 min to initial rate until infusion is complete. 
If symptoms recur, at lowest infusion rate stop the infusion and no further Interferon Alpha-
2b administered on that day. If symptoms recur after the rate has been increased, stop the 
infusion, treat reaction as per institutional guidelines, consider dexamethasone 20 mg IV 
and restart at 66% slower rate (over 1 hour) without up-titration. Future doses pre-treatment 
modifications and rate modifications after discussion with the investigator. Record toxicity.

Severe life-threatening symptoms (e.g., hypotension requiring pressor therapy, 
angioedema, respiratory distress requiring bronchodilation therapy, generalized urticaria): 
Stop infusion. Treat as per institutional guidelines. Subject should be removed from further 
protocol therapy. Report as serious adverse event.

In case of observation of toxicities which will require removal of any of the initial 3 
patients, in additional patients we will suspend the PD-1/PD-L1 blockade of the 12 week 
duration of the experimental treatment and resume it (alone or combined with either 
CTLA4- or LAG3 blockade) at week 12.
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11 PROCEDURES INVOLVED
The study-specific assessments are outlined in Appendix I (Schedule of Procedures and 
Observations). Unless otherwise stated on the study calendar, Baseline and/or Screening 
assessments must be performed within 28 days prior to the first cycle of the treatment regimen. 
Any results falling outside of the reference ranges may be repeated at the discretion of the 
investigator.
Unless otherwise defined in the written protocol text, all procedures/assessments will be conducted 
in accordance with Roswell Park Clinical Trials Office Standard Operating Procedures.
Eligibility of each participant will be established prior to start of treatment.
Informed consent MUST be completed prior to receiving any study related procedures.
Pre-screening

Buccal swab (or peripheral blood) for HLA-A2 testing. 
HLA-A2 positivity is required for study eligibility. Samples for HLA-A2 typing for eligibility will 
performed by a CLIA certified laboratory, as selected by site. 
Note: Participant must sign a separate informed consent prior to HLA testing.
Other than the HLA testing, the rest of the screening tests (as indicated in Appendix I) will be 
carried out after confirmation of HLA eligibility and informed consent and, are to be completed 
within 28 days prior to Cycle 1-Day 1 of the CKM regimen. Any results falling outside of the 
reference ranges may be repeated at the discretion of the investigator.
11.1 Post-Treatment Follow-Up Evaluations
To capture all possible delayed immune-related adverse events, follow-up safety evaluations will 
occur at least monthly for 90 days after last dose of study drug or until resolution of any drug-
related toxicity (telephone contact is acceptable).

Concomitant medications: List any ongoing medications with dose changes, as applicable.

Adverse events

Survival status
11.2 Long-Term Follow-Up Evaluations
After 90-day post treatment follow-up visit, participants will be followed within the scope of 
standard of care to assess survival status (e.g., every 3 months or according to institutional 
guidelines if patient starts on an alternative therapy). Participants who are unavailable for follow-
up evaluations should be classified as lost to follow-up for 1 of the following reasons:

Lost to follow-up: For a participant to be considered lost to follow-up, the investigator must 
make two separate attempts to re-establish contact with the participant. The attempts to re-
establish participant contact must be documented (e.g., certified letter).

Death: Date and cause of death will be recorded for those participants who die within 
30 days after last dose of study drug (telephone verification is acceptable).
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11.3 Correlative Studies
The correlative studies will involve testing to be performed by the Kokolus lab (within their scope), 
depending on the available funding.
11.3.1 Fresh Biopsy Specimens
A fresh biopsy is required at the following time points:

Baseline (prior to Cycle 1)

Week 11
At each time point, we will obtain 4 core biopsies of the tumor and 1 core biopsy of the surrounding 
non-tumor tissue. Samples are to be labeled with the study-specific subject ID number, the clinical 
study number, the protocol time-point and protocol day. One (1) core of tumor tissue for research 
will be placed in formalin and sent to Clinical Research Laboratory Services for FFPE processing. 
Dr. Kokolus’s lab will be notified when a block is available for pick-up. Blocks will be stored in 
Dr. Kokolus’s lab for future analysis. The remaining 3 cores of the tumor tissues and the core of 
non-tumor tissue will be placed in cold Dulbecco’s Phosphate-Buffered saline and kept on wet ice 
for delivery to the Kokolus lab within 2 hours of collection (a maximum of within 4 hours of 
collection is allowed). Samples will then be cryopreserved and stored in Dr. Kokolus’s lab until 
analysis.
Roswell Park Comprehensive Cancer Center
Kokolus Laboratory (Attn: Ronald Slomba)
CCC Building Room 410-416
(Tube Station: 641)
Direct Phone: 716-845-3126
Lab Phone: 716-845-1300, ext. 1816
Cell Phone: 716-400-6222 
Attn: Study Number: I 82419
Elm & Carlton Streets
Buffalo, NY 14263
Ronald.Slomba@ RoswellPark.org
Kathleen.Kokolus@RoswellPark.org
Marija.Vujcic@RoswellPark.org
Duna.Massillon@RoswellPark.org
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
11.3.2 Blood Samples for Correlative Analysis
Blood samples will be collected via venipuncture for immune biomarker analysis. Samples will be 
collected using 6, 10 mL green-top heparinized tubes.
Samples for correlative analysis will be obtained on:
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
Day 1 and Day 3 of Cycles 1, 2, 3 and 4
o
Pre-infusion and,
o
1 hr (± 10 minutes) post-rintatolimod infusion

End of Treatment (± 3 days)

Week 12 (± 1 week)
Tubes will be labeled with the participant’s MR number, participant’s initials, participant’s study 
number, clinical study number, time of collection and protocol day. Samples will be sent at room 
temperature to the attention of Clinical Research Laboratory Services (pneumatic Station 19) 
where they will get accessioned for tracking. Once specimen receipt has been documented, the 
specimens will be sent at ambient temperature to pneumatic station 641 (located in CCC LOB-4th 
floor). The Kokolus Laboratory will be notified via telephone and e-mail (all contacts to be copied 
with each e-mail: see contact information below) prior to sample shipment and, the samples will 
be held in Clinical Research Laboratory Services until a response is received acknowledging that 
personnel are available to procure the samples from the pneumatic tube station. Samples will be 
processed and stored in the Kokolus Laboratory for future analysis.
Roswell Park Comprehensive Cancer Center
Kokolus Laboratory (Attn: Ronald Slomba)
CCC Building Room 410-416
(Tube Station: 641)
Direct Phone: 716-845-3126
Lab Phone: 716-845-1816
Cell Phone: 716-400-6222 
Attn: Study Number – I 82419
Elm & Carlton Streets
Buffalo, NY 14263
Ronald.Slomba@ RoswellPark.org
Kathleen.Kokolus@RoswellPark.org
Marija.Vujcic@RoswellPark.org
Duna.Massillon@RoswellPark.org
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
12 WITHDRAWAL OF SUBJECTS
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, or 
until abnormal laboratory findings have returned to acceptable or pre-study limits. The final status 
of the AE will be reported in the participant’s medical records and the appropriate eCRF.
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Reasons for treatment discontinuation should be classified as follows:

Death

Progressive disease

Toxicity; treatment related or unrelated

Investigator judgment
o
The Investigator may discontinue a participant if, in his/her judgment, it is in the 
best interest of the participant to do so.

Noncompliance

Participant voluntary withdrawal
o
A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain information 
regarding the reason for withdrawal.
12.1 Replacement

Participants will be withdrawn from the study and replaced if 1) they do not meet the 
remaining eligibility requirements after having been tested as HLA-A2 positive, 2) if after 
a second leukapheresis (if required), a sufficient number of cells for 3 intradermal αDC1 
cell-based injections and proposed QC testing are not obtained and if 3), the patient 
withdraws prior to Cycle 1-Day 1, there is evidence of disease progression from time of 
enrollment until prior to Cycle 1-Day 1 or, physician’s decision to withdraw the patient 
prior to the start of the treatment regimen.

A participant will be deemed unevaluable for the primary analysis (i.e., response 
evaluation at Week 12) if they have not completed 3 treatment cycles (Cycle 1: CKM only 
and Cycles 2-3: αDC1 cell-based treatment +CKM). One missed cycle is allowed.
13 RISKS TO SUBJECTS
Potential risks associated with patient treatment include:

DC-based therapy (development of autoimmune diseases such as vitiligo, development of 
allergic reaction to the cellular therapy)

Leukapheresis (anemia, numbness, chills, abdominal cramps, nausea, vomiting, local pain 
at site of venipuncture, and allergic reaction to topical anesthetic)

IFN alpha-2b (fever, chills, flu-like symptoms, loss of appetite, nausea, vomiting, diarrhea, 
abdominal pain, fatigue, lowered white blood count, lowered platelets with increased 
bruising/bleeding, hair loss, drowsiness; behavioral alterations, numbness and/or tingling 
in the hands and/or feet, skin rashes, inflammation of the pancreas)

Celecoxib (dyspepsia, headaches, elevated liver function tests)

Rintatolimod (mild flu-like symptoms, transient headache, fever, myalgia, arthralgia, 
injection site reaction, pruritus, vasodilation, diarrhea, and fatigue/malaise)

Venipuncture (mild pain, discomfort, bruising at the needle insertion site, inflammation of 
the vein, possible infection and bleeding)
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
Tumor Biopsy (pain, discomfort, and/or soreness at the site where biopsy was done. The 
soreness is generally diminished within 48 hours of the procedure)
14 POTENTIAL BENEFITS TO SUBJECTS
This Phase II trial is designed to determine potential efficacy of the αDC1/TBVA cell-based 
treatment combined with the CKM (rintatolimod, IFN alpha-2b and celecoxib) regimen. The CKM 
regimen has proven to be safe and well-tolerated by colorectal cancer patients in ongoing trials. 
The CKM regimen is anticipated to facilitate the direction of anti-TBVA/anti-tumor T cells into 
melanoma tissue, potentially leading to the induction of tumor regression and prolonged patient 
survival. The full potential benefit to the subjects however is not known. 
This study will allow us to gain a greater understanding of the anti-tumor immune responses in the 
TME and may demonstrate advantage of potential treatments with αDC1/TBVA cell-based 
treatment and CKM in patients receiving concurrent anti-PD1 or anti-PD-L1. Although, based on 
our previous preclinical and clinical experience, we anticipate that αDC1/TBVA cell-based 
treatment plus CKM may be partially effective by themselves, the inclusion of continued immune 
checkpoint blockade in combination with αDC/CKM -based treatment protocol is expected to 
result in optimal improve anti-tumor efficacy.
15 DATA AND SPECIMEN BANKING
All samples for correlative analysis will be sent to Dr. Kokolus’s Laboratory for processing (CCC-
410-416). Samples will be used for planned study assays as well as for future analysis for other 
yet to be identified biomarkers that may be related to the clinical outcome of the study population. 
Any clinical data that is associated with the samples, will be stored on a secure server in the 
Department of Medicine, will be accessible only by the PI, Co-Investigators and PI designated 
data manager and, will be password protected. All computer entry and networking programs will 
be done using PIDs only. Any clinical data and/or specimens for future research will require 
verification of an IRB-approved protocol and will be de-identified before being released.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
16 MEASUREMENT OF EFFECT
Objective response rate and progression will be evaluated at Week 12 (primary objective) using 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) (22). 
Please refer to Appendix F for a summary of tumor response assessment according to RECIST 1.1 
criteria.
Response and progression following Week 12 will be evaluated in this study using the immune-
related response criteria (iRECIST): Please refer to Appendix G.
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For the purposes of this study, patients should be re-evaluated for recurrence or progression of 
disease using CT scan as the primary modality. Other imaging modalities are allowed based on 
clinical circumstances (e.g. CT contrast allergy). 
In addition to the scans during the treatment phase of the protocol, CT scans should also be 
obtained during the follow up period in accordance with standard of care, but no later than every 
8-12 weeks following initial documentation of objective response.
Note: The following section on response and stable disease duration is part of the original 
submission (supplementary appendix) by Seymour et al, 2017(20) and has been peer reviewed. 
16.1 Response and Stable Disease Duration (RECIST 1.1 and iRECIST)
Response duration will be measured from the time measurement criteria for CR/PR or iCR/iPR 
(whichever is first recorded) are first met until the first date that recurrent or progressive disease 
is objectively documented, taking as reference the smallest measurements recorded on study 
(including baseline).
Stable disease duration will be measured from the time of start of treatment until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline).
16.2 Methods of Measurement
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. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy. While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. 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. 
For lesions which fragment/split add together the longest diameters of the fragmented portions; 
for lesions which coalesce, measure the maximal longest diameter for the “merged lesion”.
16.2.1 Clinical Lesions
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm as 
assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended. If feasible, 
imaging is preferred.
16.2.2 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 
≥20 mm on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung.
16.2.3 CT, MRI
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater 
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than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). Other specialized imaging or other 
techniques may also be appropriate for individual case.4 For example, while PET scans are not 
considered adequate to measure lesions, PET-CT scans may be used providing that the measures 
are obtained from the CT scan and the CT scan is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast).
16.2.4 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 is advised.
16.2.5 Endoscopy, Laparoscopy
The utilization of these techniques for objective tumour evaluation is not advised. However, they 
can be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response or surgical resection is 
an endpoint.
16.2.6 Tumor Markers
Tumour markers alone cannot be used to assess objective tumour response. If markers are initially 
above the upper normal limit, however, they must normalize for a patient to be considered in 
complete response.
16.2.7 Cytology, Histology
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in tumour types such as germ cell tumors, where known 
residual benign tumors can remain). When effusions are known to be a potential adverse effect of 
treatment (e.g., with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment 
when the measurable tumour has met criteria for response or stable disease is advised to 
differentiate between response or stable disease and progressive disease.
17 SAFETY EVALUATION
17.1 Adverse Events
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
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17.2 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
17.3 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
17.4 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated blood potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
17.5 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
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17.6  Grading and Reporting Adverse Events
Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 5 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 5.0 of the CTCAE is identified and located at:
http:// ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50.
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE Version 5.
The relationship of event to study drug will be documented by the Investigator as follows:
Unrelated: The event is clearly related to other factors such as the participant’s clinical state, other 
therapeutic interventions or concomitant drugs administered to the participant.
Unlikely: The event is doubtfully related to investigational agent(s). The event was most likely 
related to other factors such as the participant’s clinical state, other therapeutic interventions, or 
concomitant drugs.
Possible: The event follows a reasonable temporal sequence from the time of drug administration 
but could have been produced by other factors such as the participant’s clinical state, other 
therapeutic interventions or concomitant drugs.
Probable: The event follows a reasonable temporal sequence from the time of drug administration 
and follows a known response pattern to the study drug. The event cannot be reasonably explained 
by other factors such as the participant’s clinical state, therapeutic interventions or concomitant 
drugs.
Definite: The event follows a reasonable temporal sequence from the time of drug administration, 
follows a known response pattern to the study drug, cannot be reasonably explained by other 
factors such as the participant’s condition, therapeutic interventions or concomitant drugs; AND 
occurs immediately following study drug administration, improves upon stopping the drug, or 
reappears on re-exposure.
Reporting Adverse Events
Routine AEs occurring between the starting date of the intervention until 30 days after the last 
intervention, or until the event has resolved, the study participant is lost to follow-up, the start of 
a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
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Guidelines for Routine Adverse Event Reporting for Phase II Studies (Regardless of 
Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
17.7 Serious Adverse Events
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death.

A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from the 
reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed above.
Reporting Serious Adverse Events
All new SAEs occurring from the date the participant signs the study consent until 30 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
Roswell Park SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information. 
SAEs occurring after the 30 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAEs that are unexpected and possibly, probably or definitely related must be reported as an 
Unanticipated Problem. Please refer to Section 17.10 for details on reporting Unanticipated 
Problems.
17.8 Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received.
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17.9 Unanticipated Problems
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
o
The research procedures that are described in the study-related documents, 
including study deviations, as well as issues related to compromise of participant 
privacy or confidentiality of data.
o
The characteristics of the participant population being studied.

Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research).

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 17.7.
Reporting Unanticipated Problems
The Reportable New Information (RNI) Form will be submitted to the CTO Quality Assurance 
(QA) Office within 1 business day of becoming aware of the Unanticipated Problem. After review, 
CTO QA Office will submit the RNI to the IRB.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CTO QA Office with an updated Reportable New Information Form. The site 
Investigator or designated research personnel will report all unanticipated problems to the IRB in 
accordance with their local institutional guidelines.
17.10 FDA Reporting
When Roswell Park is the IND holder the following describes the FDA reporting requirements by 
timeline for AEs and new safety findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Fatal or life-threatening.
Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Serious but not fatal or life-threatening;
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Or, meets ANY of the following criteria:

A previous adverse event that is not initially deemed reportable but is later found to fit 
the criteria for reporting (report within 15 days from when event was deemed 
reportable).

Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.

Any findings from animal or in vitro testing that suggest a significant risk for human 
participants including reports of mutagenicity, teratogenicity, or carcinogenicity or 
reports of significant organ toxicity at or near the expected human exposure.

Any clinically important increase in the rate of occurrence of a serious, related or 
possibly related adverse event over that listed in the protocol or investigator brochure.
Sponsors are also required to identify in IND safety reports, all previous reports concerning similar 
adverse events and to analyze the significance of the current event in the light of the previous 
reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A MedWatch 
for any event that meets the above criteria. Forms will be submitted to the CTO QA Office via 
email to CTO-QA@RoswellPark.org.
18 DATA MANAGEMENT AND CONFIDENTIALITY
18.1 Data Collection
Full build studies are managed by Roswell Park CTO Data Management for analysis by Roswell 
Park Biostatisticians. All electronic case report form (eCRF) data are captured for these studies.
Data management activities are performed using a CTMS system that enables the collection, 
cleaning and viewing of clinical trial data. CTO data management designs the study-specific 
database and facilitates development by the Information Technology team. Once the database 
design is approved by the Investigator, Statistician, and Clinical Research Coordinator, the 
database is put into production and data entry can begin. Data can be entered and changed only by 
those with the rights to do so into the eCRFs.
18.2 Maintenance of Study Document
Essential documents will be retained per Roswell Park’s policy for 6 years from the study 
termination date. These documents could be retained for a longer period, however, if required by 
the applicable local regulatory requirements or by an agreement with Roswell Park.
18.3 Revisions to the Protocol
Roswell Park may make such changes to the protocol as it deems necessary for safety reasons or 
as may be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to 
the IRB/ERC for written approval before implementation.
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18.4 Termination of the Study
Roswell Park may terminate the study at any time upon immediate notice if it believes termination 
is necessary for the safety of participants enrolled in the study.
19 STATISTICAL PLAN
19.1 Demographic and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics.
19.2 Study Duration and Compliance 
All study drug administration and compliance data will be summarized.
19.3 Prior and Concomitant Medication 
All relevant prior medication and all concomitant medications will be summarized by frequencies 
and percentages.
19.4 Safety evaluations.
For the initial 3 patients, safety will constitute the formal primary endpoint. Overall safety profile 
will be characterized by type, frequency, severity (according to CTCAE version 5.0), timing, 
seriousness, and relationship to study treatment. Please see detailed description in points 19.10 and 
19.11 below. The initial 3 patients will receive a reduced dose of IFNα2b (10MU/mM2), to obtain 
initial safety confirmation for the new source of IFNα2b. In the absence of dose-limiting adverse 
effects, we will proceed to use the full dose of IFNα2b (20MU/M2) in the CKM regimen. In case 
of dose limiting toxicities, we will suspend accrual and consult the IRBN and FDA for the 
development of extended safety plan and protocol revision.
19.5 Efficacy Analyses
This trial is designed as a single arm phase II trial of a type-1 polarized dendritic cell (DC1)-
based treatment in combination with tumor-selective chemokine modulation (CKM: Interferon-
a2b, Rintatolimod and Celecoxib) in melanoma patients with primary PD-1/PD-L1 resistance. The 
primary endpoint is ORR at 12 weeks. The maximum sample size will be n=24. 
The primary test of efficacy will be carried out by an exact binomial test of a proportion within a 
Simon two-stage design. The study design stops early for futility only. We will test that the null 
ORR = 0.20 versus the alternative ORR > 0.20, which leads to the following decision rule: 
Stage 1: If 2 or less of the first n1 = 14 evaluable subjects have an OR, it will be concluded that 
the therapy and the study will end due to futility. Otherwise, the study will continue to the second 
stage.
Stage 2: We will accrue 10 additional subjects. If 8 or more of the total of n1 + n2 = 24 evaluable 
subjects have an OR, it will be concluded that the therapy is promising; otherwise, it will be 
concluded that the therapy is not worthy of further study. 
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19.6 Sample Size Determination
The nominal significance level of this design is alpha=0.10. The sample size calculation is based 
on testing the hypotheses concerning the proportion of the population with a response to the 
treatment. This two-stage design requires a maximum of n=24 in order to achieve approximately 
1-beta=0.80 power to detect differences of 0.20 percentage points greater than the null 
hypothesized value of a 0.20 ORR at six months.
19.7 Secondary Analyses
We will evaluate the immune-related objective response rate (ORR; per iRECIST;) in patients that 
continue on with either PD-1/PD-L1 and/or CTLA4 blockade after meeting the 12-week primary 
objective treated with autologous αDC1/TBVA cellular treatment plus cytokine CKM regimen 
followed by re-treatment with PD-1/PD-L1 blockade (± CTLA4 blockade). In addition, we will 
evaluate rate of durable responses (> 6 months) on the combination treatment in the above patient 
population treated with autologous αDC1/TBVA cellular treatment plus cytokine CKM regimen 
followed by re-treatment with PD-1/PD-L1 blockade (± CTLA4 blockade). The analysis will be 
primarily descriptive and consist of sample proportions and the corresponding 95% confidence 
intervals.
19.8 Exploratory Analyses
Exploratory endpoints are to examine whether the combination of peptide-loaded autologous 
αDC1 cellular therapy and tumor-selective chemokine modulation with IFN-a2b, rintatolimod, and 
celecoxib improves the OS and irPFS in HLA-A2+ subjects PD-1/PD-L1-refractory melanoma 
compared to the historical control of the best supportive care and to identify the intratumoral and 
systemic immune correlates of the response to treatment. Time-to-event endpoints will be analyzed 
by a Cox regression model as a function of various biomarker combinations.
19.9 Randomization
This is a non-randomized study.
19.10 Safety and Toxicity Analyses 
Adverse events monitoring and clinical findings including physical examinations, vital signs, 
laboratory test results, concomitant medications, and withdrawals/terminations will be used to 
assess safety.
19.11 Adverse Events and Serious Adverse Events 
AEs will be categorized by SOC and Preferred Terms as per CTCAE version 5.0. The incidence 
of AEs as well as the severity and relationship to study drug will be presented and the incidence 
of AEs leading to withdrawal from the study and serious AEs (SAEs) will be summarized by 
frequency and percentages.
As per NCI CTCAE Version 5.0, the term toxicity is defined as adverse events that are classified 
as either possibly, probably, or definitely related to study treatment. The maximum grade for each 
type of toxicity will be recorded for each patient and will be used for reporting. Frequency tables 
will be reviewed to determine toxicity patterns. In addition, all adverse event data graded as 3, 4, 
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or 5 and classified as either “unrelated or unlikely to be related” to study treatment in the event of 
an actual relationship developing will be reviewed.
Serious adverse events will be similarly summarized. Clinical findings will include evaluation of 
physical examinations, vital signs and laboratory test results, concomitant medications, and 
withdrawals/terminations.
19.12 Procedure for Accounting for Missing, Unused and Spurious Data 
Missing data will be indicated in the listings, but excluded from all descriptive analyses. All data 
will be listed, including otherwise unused data. Spurious data will be identified as such, wherever 
possible.
20 PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF 
SUBJECTS
Patients will be monitored at intervals as stipulated in the Study Calendar and/or dictated by 
standard care. Appropriate care will be provided to any patients experiencing difficulty while being 
treated, and patients are encouraged in the consent forms to report adverse experiences to the 
investigator/sub-investigator. This information is collected per the protocol, and treatment is 
administered as needed. Patients will be advised regarding the importance of reporting any side 
effects to their investigator/sub-investigator or the study coordinator so that the appropriate 
medical treatment can be administered to prevent life threatening or fatal adverse events. Study 
treatment will be immediately discontinued for any grade IV toxicity that becomes apparent. 
Treatment will be held for any grade III toxicity pending reversal of such toxicity. In the event of 
any adverse effect, appropriate medical treatment will be instituted and study treatment will be 
discontinued if the above toxicity remains. The results of all study tests will be discussed with the 
patient and this information will be protected under University, Hospital, and federal HIPAA 
policies. Medical records will be considered confidential and are stored in a locked cabinet in the 
administrative office of Dr. Igor Puzanov. The only persons with access to these records will be 
the clinical principal investigator and his medical team, representatives of the NCI, the U.S. Food 
and Drug Administration (FDA), the National Institutes of Health (NIH), and the Roswell Park 
Cancer Institute Protocol Review and Monitoring Committee and Institutional Review Board 
(IRB). Patients will not be identified in any report or publication of this study or of its results 
without prior written permission. A comprehensive Data Safety Monitoring Plan (DSMP) is 
available for all patients involved in clinical research studies at Roswell Park. If patients are injured 
due to their participation on trial, immediate medical care will be provided by the clinical PI and 
resources of Roswell Park as outlined in the informed consent document.
The Roswell Park Data Safety Monitoring Committee will assess the progress of the study, the 
safety data, and critical efficacy endpoints (Phase I studies will be reviewed quarterly Phase II, III 
and pilot investigator-initiated studies will be reviewed semi-annually). The DSMC will review 
the study and will make recommendations that include but not limited to; (a) continuation of the 
study, (b) modifications to the design, (c) suspension of, or (d) or termination of the study.
21 VULNERABLE POPULATIONS
Not Applicable.
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22 COMMUNITY-BASED PARTICIPATORY RESEARCH
Not Applicable.
23 SHARING OF RESULTS WITH SUBJECTS
Individual response data is shared with the participant as a part of their clinical care.
24 SETTING
Participants will be identified/recruited/screened from patients at the Melanoma Clinic at Roswell 
Park, referring physicians and, from multi-disciplinary conference discussion.
Potential subjects will be identified by the examining physician and referred for evaluation by the 
principal investigator or co-investigators. Informed consent will be obtained on all subjects by the 
principal investigator or co-investigators or other designee prior to all screening procedures. No 
patient will be entered into the clinical trial without having a signed written consent form. The 
Clinical Research Coordinator will screen the subjects further, as per study PI orders, to determine 
if they would meet the inclusion/exclusion criteria.
25 PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF SUBJECTS
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
26 RESOURCES AVAILABLE
Production of αDC1/TBVA cells for the trial will take place at the cGMP cell production facility 
(Therapeutic Cell Production Facility; TCPF) of the Center for Immunotherapy (CFI) at Roswell 
Park.
This study will be performed under the IND held by Roswell Park, modified active BB-IND 
16,704, covering the combination of αDC1/TBVA cell-based treatment (DC1s loaded with tumor 
blood vessel-related antigens) and systemic CKM regimen (i. v. rintatolimod and IFN alpha-2b, 
combined with oral celecoxib). This IND was transferred to Roswell Park in mid-December 2017.
The transfer of the IND and the development of the clinical MTA and non-commercial use license 
for the use of Dr. Storkus' (University of Pittsburgh) peptides at Roswell Park (finalized in January 
2018), allows us to extend the scope of the BB-IND 16,704 to include DC production for 
melanoma patients at Roswell Park.
Since Dr. Storkus holds a related active BB-IND 15,224, which covers the same DC1/TBVA 
cell-based treatment, but combined with dasatinib (melanoma trial NCT01876212/UPCI 12-048), 
we also needed a clinical data-sharing agreement relevant to both trials, to assure appropriate 
reporting of safety and efficacy of all studies involving DC1/TBVA cell-based treatment, at both 
Institutions
Pawel Kalinski, MD, PhD. is Professor, Department of Obstetrics, Gynecology & Reproductive 
Sciences University of Pittsburgh School of Medicine and Vice Chair of Translational Research 
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Development in Women’s Health Magee-Women’s Research Institute. Dr. Kalinski will receive 
de-identified data related to patients enrolled for the purpose of writing papers for publication. Dr. 
Kalinski will be receiving analyzed data for genomic profiling (via OmniSeq) and expression of 
RNA message (via RT-qPCR using TaqMan technology). Dr. Kalinski may work with Dr. 
Kokolus and Roswell lab team in review/interpretation of data. At this time, the trial is closed to 
accrual. The role of the external collaborator is to review aggregate data summary reports that have 
been deidentified and they will never have access to identifiable data. The Roswell Park legal 
department will ensure proper sharing agreements are in place with the University of Pittsburgh 
School of Medicine. Local IRB approval will be obtained from the University of Pittsburgh School 
of Medicine.
27 PRIOR APPROVALS
Pending: It is anticipated that the trial will be activated within 6 months of receiving NIH funding 
28 COMPENSATION FOR RESEARCH-RELATED INJURY
If the subject believes they have been injured as a direct result of their participation in this research 
study, they will be advised to notify the Roswell Park Patient Advocate at (716) 845-1365 or the 
Study Doctor at (716) 845-7505.
Medical diagnosis and treatment for the injury will be offered, and a determination will be made 
regarding appropriate billing for the diagnosis and treatment of the injury. A financial counselor 
(716-845-4782) will be able to provide an explanation of coverage and to answer questions the 
subject may have regarding study related billing.
The subject is not prevented from seeking to collect compensation for injury related to malpractice, 
fault, or blame on the part of those involved in the research.
29 ECONOMIC BURDEN TO SUBJECTS
The participants will not be subject to any economic burden.
30 CONSENT PROCESS
The Roswell Park SOP: Informed Consent Process for Research (HRP-090) will be followed:
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the investigator to ensure that the participant is made aware of the investigational 
nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
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This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices.
31 PROCESS TO DOCUMENT CONSENT IN WRITING
The Roswell Park “SOP: Written Documentation of Consent (HRP-091)” will be followed:
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant in accordance with GCP guidelines using the approved informed consent form, before 
any study specific procedures (including screening procedures) are performed. The informed 
consent form acknowledges all information that must be given to the participant according to 
applicable GCP guidelines, including the purpose and nature of the study, the expected efficacy 
and possible side effects of the treatment(s), and specifying that refusal to participate will not 
influence further options for therapy. Any additional information that is applicable to the study 
must also be included. Additional national or institutionally mandated requirements for informed 
consent must also be adhered to. The participant should also be made aware that by signing the 
consent form, processing of sensitive clinical trial data and transfer to other countries for further 
processing is allowed.
The Investigator or designee shall provide a copy of the signed consent form to the participant and 
the signed original shall be maintained in the Investigator File. A copy of the signed consent form 
must be filed in the participant file. At any stage, the participant may withdraw from the study and 
such a decision will not affect any further treatment options.
32 DRUGS OR DEVICES
Roswell Park will hold the IND for this study.
IND NUMBER: BB-IND 16,704
32.1 Celecoxib
A sulfa non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, 
rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce 
numbers of colon and rectum polyps in patients with familial adenomatous polyposis.
32.1.1 Other Names
Celebrex, Celebra or Onsenal (commercially available)
32.1.2 Formulation and packaging
Celecoxib as capsules in the following dosages: 100 mg and 200 mg.
32.1.3 Drug Shipment
Celecoxib will be provided by Roswell Park (to be purchased with grant or startup funding).
32.1.4 Drug administration
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Celecoxib 200mg will be administered orally twice a day approximately 12 hours apart on Days 
1-3 of Cycles 1-4). The morning dose will be given to the participant at the same time as the other 
pre-medications for the CKM regimen. The evening dose of Celecoxib will be self-administered 
by the participant at home and documented on the patient diary Appendix H).
32.1.5 Drug Storage and accountability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited access facility in accordance with the applicable 
regulatory requirements.
Celecoxib is to be stored at room temperature (20-25°C), away from light and moisture. Brief 
storage between 59-86 °F (15-30 °C) is permitted.
Drug storage temperature will be maintained and recorded, as applicable.
32.2 Interferon Alpha-2b (Bioferon, replacing the discontinued INTRON-A)
32.2.1 Active Substance and Source
Interferon α-2b (BIOFERON®) is supplied in a single-dose vial containing sterile lyophilized 
powder. Each vial contains 10 million lnternational Units (MIU) of recombinant human interferon 
alfa 2b, glycine, dibasic sodium phosphate dodecahydrated, monobasic sodium phosphate 
anhydrous and human albumin. For its administration, lyophilized powder should be reconstituted 
by adding 1mL of sterile water for injection. Bioferon® is not FDA-approved and is considered 
an investigational new drug in the United States.
32.2.2 Drug Shipment
Interferon α-2b (Bioferon®) will be provided by Biosidus S.A. and shipped to the Roswell Park 
IDS.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
How supplied: Vial containing 10 million Units r-Hu-IFN α-2b freeze dried powder. Each package 
contains 1 solvent ampule with 1 mL sterile WFI.
32.2.3 Preparation
The lyophilized product is reconstituted as directed by the manufacturer. Investigational Drug 
Service Pharmacy (IDS) will prepare and dispense.
10 million units/mL, lyophilized powder, which must be reconstituted prior to administration.

Vial size: 10 million units/vial

Diluent: Interferon α-2b (Bioferon®) should be reconstituted with 1 mL sterile water 
to reach a final concentration of 10:1. IV dose should be diluted in sodium chloride 
0.9%/100 mL given over 30 minutes. The final concentration of interferon α-2b 
should not be less than 10 million units/100 mL.
Once reconstituted, mix the suspension with gentle rotation movements, do not shake vigorously.
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For IV injection, it is recommended that Interferon α-2b be administered as a solution of no less 
than 10 million units/100 mL to minimize adsorption of the drug to glass and plastic containers.
32.2.4 Storage and Stability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, as specified and in accordance with the 
applicable regulatory requirements.
Interferon α-2b (BIOFERON®) should be kept refrigerated (2 - 8 °C). Do not freeze. Do not freeze 
the ampoule containing water for injection since it can leak. Once the Interferon α-2b is 
reconstituted, it should be used within the following 24 hours, storing the solution refrigerated (2 -
 8⁰C) and following strict aseptic conditions during powder reconstitution. 
Vials containing reconstituted solution should be used within two hours if they are kept at room 
temperature, or within 24 hours if they are stored at 2 - 8⁰C. 
This preparation does not contain preservative agents. Therefore, it is advisable not to extract more 
than one dose from the vial to prevent contamination. Do not use this medication after the expiry 
date printed in its container.
Drug storage temperature will be maintained and recorded, as applicable.
32.2.5 Drug Administration
Interferon α-2b (10 million units/M2 or 20 million units/M2) will be administered intravenously 
over 30 minutes during all CKM cycles.
32.2.6 Concomitant Medications
Interactions between Interferon α-2b and other drugs have not been fully evaluated. Caution should 
be exercised when administering Interferon α-2b therapy in combination with other potentially 
myelosuppressive agents such as zidovudine. Concomitant use of Interferon α-2b and theophylline 
decreases theophylline clearance, resulting in a 100% increase in theophylline levels. Concomitant 
Interferon α-2b and REBETOL® (Ribavirin) use is contraindicated. 
32.3 Rintatolimod (poly IC analog)
A substituted double stranded polyribonucleic acid (polyI: polyC12U), rintatolimod preserves 
activity of polyIC with a much improved systemic toxicity profile. The product has been studied 
extensively for use as a cellular treatment adjuvant and for its direct antiviral activity, as well in 
several cancer studies as a monotherapy, but most extensively in chronic fatigue syndrome (CFS).
32.3.1 Other Names
polyIC12U, Ampligen®, poly I: polyC12U; Polyinosinic: polycytidylic-polyuridylic acid; 
polyriboinosinic/polyribocytidylic (uridylic) acid
32.3.2 Formulation and Packaging
Rintatolimod is supplied as a liquid solution in glass bottles containing 200 mg (100 mg in case of 
toxicity) per 80 mL. Rintatolimod is a colorless solution containing 2.5 mg/mL in physiological 
salts (0.15 M NaCl, 0.01 M phosphate, 0.001 M Mg++). The product does not contain 
preservatives or antioxidants.
32.3.3 Drug Shipment
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Rintatolimod will be provided by Hemispherix and shipped to the participating site.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
32.3.4 Preparing ad Dispensing
A vial of rintatolimod is suitable for direct IV infusion. IDS will prepare and dispense. Each vial 
should be taken from the refrigerator and allowed to equilibrate to room temperature.
32.3.6 Drug Administration
Rintatolimod 200 mg will be administered by intravenous infusion after Interferon Alpha-2b on 
Days 1-3 of Cycles 1-4 of the CKM regimen. Additional details on the procedures for receiving, 
storing and using rintatolimod (Ampligen®) can be found in a separate document entitled 
“Procedures for Receiving, Storing, and Using Ampligen® (Poly I:Poly C12U) Liquid Solution”. 
The initial administration should begin at a slow rate of infusion (approximately 20 cc/ hour) and 
increase to 40cc/hour after 30 minutes. Tubing should be flushed with 30 to 50 mL of normal 
saline solution upon completion.
32.3.7 Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by Hemispherix exercising accepted medical and pharmaceutical 
practices. Study drugs must be handled as cytotoxic agents and appropriate precautions taken per 
the institution’s environmentally safe handling procedures. All investigational drugs will be 
dispensed in accordance with the Investigator’s prescription or written order.
All products dispensed will be recorded on a product accountability record. Records of product lot 
numbers and dates received will be entered on a product accountability form. This record will be 
reviewed by the Sponsor’s staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Used vials (excess drug) will be destroyed according to standard practices after properly 
accounting for the dispensing. Partially used vials of study drug will not be re-used for other 
participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
In regard to drug receipt, accountability and storage, SOP IDS-601 will be followed.
32.4 Alpha-DC1/ TBVA Cellular Product
The αDC1 cellular product will be produced accordingly to the currently active IND sponsored by 
Roswell Park. Please refer to Section 2 (Background) for the description of the cellular treatment 
production and the preclinical and early clinical experience with DC1/TBVA cell-based 
treatments and other DC1-based cellular treatments.
32.4.1 Active Substance and Source
Dendritic cells (DC) are derived from autologous (the patient’s own) adherent mononuclear cells 
(monocytes) in the peripheral blood by 5-day or 6- day culture in the presence of interleukin 4 (IL-
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4) and granulocyte-macrophage colony stimulating factor (GM-CSF), followed by 1 day of 
maturation.
32.4.2 Formulation
The αDC1 cell-based treatment will be manufactured at the Roswell Park cGMP Therapeutic Cell 
Production Shared resource, in a process analogous to the Roswell Park-held IND (autologous 
monocyte-derived DCs loaded with UV/gamma radiation-killed autologous tumor material). The 
αDC1 cells are prepared under cGMP conditions and the final product is vialed and cryopreserved. 
Labels placed on all tubes contain a unique cellular product lot. The αDC1 cellular product release 
will follow the quality and safety testing of the cellular product lot.
32.4.3 Packaging and Labeling
All synthesis, production, formulation and packaging of the αDC1 will be in accordance with 
applicable current Good Manufacturing Practices and meet applicable criteria for use in humans.
32.4.4 Storage and Preparation
The αDC1cellular product will be stored at the cGMP Therapeutic Cell Production Shared 
Resource and laboratory staff will be responsible for ensuring that study cellular product is 
securely maintained in accordance with the applicable regulatory requirements. The αDC1 cellular 
product storage temperature will be maintained, recorded, dated and initialed daily as applicable.
Vials containing the final product, αDC1, will be viably frozen using a controlled rate freezer and 
stored in the vapor phase of LN2 freezer located on the 4th floor of the CCC Building, in the cGMP 
suite, Therapeutic Cell Production Shared Resource at Roswell Park.
DC1s used in the cell-based treatment will be suspended in 5% human serum albumin (HSA) 
and delivered to the clinic for administration. For preparation of the αDC1 cell-based treatment, 
the labeled vials of cryopreserved αDC1 are removed from storage in liquid nitrogen and quickly 
thawed in a 37C water bath. After two washes, thawed αDC1 will be suspended in 5% HSA and 
placed in sterile syringes for intradermal or intraperitoneal administration to the patient. Each 
syringe will be labeled with a custom-designed label, identifying the patient, the cellular product, 
and the route of administration. The 5% HSA is clinical grade.
32.4.5 Stability
The αDC1 cellular product retains viability for at least 24 hours when stored in 5% HSA at 4oC 
following thawing, washing and loading onto syringes. However, we observed gradual decrease 
in IL-12p70 producing function upon prolonged storage. For this reason and to assure uniform 
quality, DC cell-based injections will be administered within 6 hours after their release.
32.4.6. Dosing and Administration
Each 0.2 mL of the αDC1 cell suspension will contain approximately 10 x 106 cells and will be 
loaded onto a single tuberculin syringe. The αDC1 cell suspension will be administered 
intradermally (i. d.) by the investigator or qualified designee. The investigator/designee will inject 
approximately 0.1 mL of the syringe contents intradermally and then will remove the needle from 
the patient. Using the same needle, the investigator/designee will then inject the remaining 0.1 mL 
of the syringe contents intradermally on the opposite side of the body (the other thigh). The upper 
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thighs are the preferred locations for the injections, however upper arms are also allowed. The 
injections will be administered within 6 hours of thawing and release (target: 2 hrs).
32.4.7 Handling and Disposal
The Investigator will be responsible for dispensing and accounting for all investigational drug 
provided by the cGMP Therapeutic Cell Production Facility at Roswell Park. All investigational 
drugs will be dispensed in accordance with the Investigator’s prescription or written order.
All products dispensed will be recorded on a product accountability record. Records of product 
receipt, date, time, and temperature will be entered on a product accountability form. Accurate 
records must be kept regarding dispensing and return of study cellular treatment, for each 
individual patient in the study. Reasons for departure from the expected dispensing or return of 
study cellular treatment must be recorded. The cellular treatment transportation container with 
temperature recorder must be returned to the cGMP Therapeutic Cell Production Facility after 
administration. The cellular treatment will be transported directly from the cGMP Facility without 
need to go to the Investigational Drug Service (IDS) in the pharmacy department.
Study drug accountability records will be available for verification by the Clinical Trials Office 
(CTO) monitor appointed from the CTO office at each monitoring visit. At the completion of the 
study, there will be a final reconciliation of all study drugs.
An investigational agent dispensing record will be kept current and will contain the following 
information:

Patient’s identification information (i.e., patient identification number and medical record 
number).

Date and quantity of drug dispensed.

Date and quantity of drug returned to the Investigator/pharmacy (if any).

Date and quantity of accidental loss of study drug (if any).
These inventories must be made available for inspection by the CTO monitor. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
At the end of the study, the CTO monitor will also collect the original investigational drug 
dispensing records. Remaining unused αDC1 cellular product will be stored at the cGMP 
Therapeutic Cell Production Facility for a period that is consistent with applicable regulations. 
Unused αDC1 cellular product will be used for laboratory research or disposed. Any disposal of 
investigational agent shall be noted on the investigational drug disposition log and signed-off by a 
second person. At the end of the study, the CTO monitor will collect the original drug disposition 
record.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
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Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, 
Verweij J. New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). European Journal of Cancer. 2009;45(2):228-47. doi: 
http://dx.doi.org/10.1016/j.ejca.2008.10.026.
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34 APPENDICES
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Appendix A
ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix B
INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
INCLUSION CRITERIA
Participant Name: _____________________________________________________________
Medical Record No.: ___________________________________________________________
Title: A Phase II Study of Type-1 Polarized Dendritic Cell (αDC1)-based Treatment in 
Combination with Tumor-Selective Chemokine Modulation (CKM: Interferon alpha-2b, 
Rintatolimod and Celecoxib) in Melanoma Patients with Primary PD-1/PD-L1 Resistance
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Age ≥ 18 years of age.
2.
Participant must be HLA-A2+, Retesting is not required for patients 
who have previous documented positivity
3.
Have IO-refractory melanoma with primary PD-1/PD-L1-resistance. 
Note: Any lines of prior therapies are allowed, but the last line needs to 
include an anti PD-1 or anti PD-L1 agent. The prior treatments may 
include any standard and/or experimental therapies.
4.
Have > 1 tumor site amenable to core needle biopsy that is not the site 
of disease used to measure antitumor response
5.
Have measurable disease based on RECIST 1.1 criteria present.
6.
Have an ECOG Performance Status of 0-2. Refer to Appendix A.
7.
Have normal organ and marrow function as defined below:

Platelets ≥ 75,000/ microliter

Hemoglobin ≥ 9 g/ deciliter

Absolute Neutrophil Count (ANC) ≥ 1000/microliter

Creatinine < 1.5 X institutional upper limit of normal (ULN) OR 
creatinine clearance ≥ 50 mL/min by Cockroft-Gault formula for 
subjects with creatinine levels ≥ 1.5 x ULN (Appendix D).

Total bilirubin not greater than 1.5 X institutional ULN, except for 
patients with known Gilberts Syndrome, who are eligible to no 
more than 2 X institutional ULN.

AST(SGOT) and ALT(SGPT) no greater than 3 x institutional 
ULN OR, no greater than 5 x ULN for subjects with liver 
metastases
8.
Participants of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth 
control; abstinence) prior to study entry. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician 
immediately.
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INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
9.
Participant must understand the investigational nature of this study and 
sign an Independent Ethics Committee/Institutional Review Board 
approved written informed consent form prior to receiving any study 
related procedure.
10. Candidate for continuation/resumption of anti-PD-1/PD-L1 blockade 
(in parallel to DC vaccine and CKM).
Investigator Signature: ___________________________________
Date: ___________
Printed Name of Investigator: __________________________________________________
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Appendix C
INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
EXCLUSION CRITERIA
Participant Name: ____________________________________________________________
Medical Record No.:___________________________________________________________
Title: A Phase II Study of Type-1 Polarized Dendritic Cell (αDC1)-based Treatment in 
Combination with Tumor-Selective Chemokine Modulation (CKM: Interferon alpha-2b, 
Rintatolimod and Celecoxib) in Melanoma Patients with Primary PD-1/PD-L1 Resistance
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Is currently being treated with systemic immunosuppressive agents, 
including steroids: Subjects will be ineligible until 3 weeks after 
removal from immunosuppressive treatments, except when they are 
administered as replacement therapy for endocrine dysfunction (and 
receive no more than 10 mg prednisone or equivalent: inhaled steroids 
are allowed.
2.
Has had prior anti-cancer therapy within 2 weeks prior to study day 1 or 
who has not recovered (i.e., no more than Grade 1 or at baseline) from 
adverse events due to a previously administered agent, except for 
neuropathy (no more than Grade 2) or alopecia or vitiligo (any grade)..
3.
Has a known additional malignancy that is progressing or requires 
active treatment.
4.
Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Treated brain metastases are allowed, if 
stable for more than 4 weeks (and receive no more than 10 mg 
prednisone or equivalent: inhaled steroids are allowed).
5.
Has a history of cardiac event(s) (acute coronary syndrome, myocardial 
infarction, or ischemia (within 3 months of signing consent) or, subject 
has a New York Heart Association classification of III or IV.
6.
Has an active infection requiring systemic therapy.
7.
Has known active Hepatitis B or Hepatitis C infection.
8.
Has known immunosuppressive disease (e.g. HIV, AIDS or other 
immune depressing disease). Testing is not mandatory.
9.
Has known serious hypersensitivity reactions to peg-interferon alpha-2b 
or interferon alpha-2b.
10. Prior allergic reaction or hypersensitivity to sulfonamides, celecoxib, or 
NSAIDs.
11. Has received a blood transfusion in the two weeks prior to 
leukapheresis.
12. Women of child bearing potential who are pregnant or nursing.
13. Unwilling or unable to follow protocol requirements.
14. Any condition which in the Investigator’s opinion deems the participant 
an unsuitable candidate to receive study drug.
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EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
15. Patients who showed initial response to PD-1/PD-L1 blockade and 
developed secondary resistance.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
Printed Name of Investigator: _________________________________________________
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Appendix D
Cockcroft-Gault Equation
Cockcroft-Gault Equation*
Men: CrCl = [(140-YR) x IBW] / (PCr x 72)
Women: CrCl = 0.85 x [(140-YR) x IBW] / (PCr x 72)
Where:
CrCl is creatine clearance (mL/min)
IBW is ideal body weight (kg)
PCr is plasma creatinine (mg/dL)
YR is age (years)
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Appendix E
NYHA CLASSIFICATION
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Appendix F
RECIST 1.1 Criteria
Objective Tumor Response
All protocol-defined imaging studies must be performed at the investigative site or sponsor-
approved facility using protocol-defined parameters. 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. RECIST 1.1 will be used to assess objective tumor response.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, will be identified as target lesions and recorded and measured at baseline. 
Target lesions will be selected on the basis of their size. Lesions with the longest diameter (short 
axis for lymph nodes) and are ≥ 10 mm (CT and MRI), ≥ 15 mm lymph nodes, > 20 mm CXR and 
are for accurate repetitive measurements (either by imaging techniques or clinically) will be 
chosen. A sum of the longest diameter (short axis for lymph nodes) of all target lesions will be 
calculated and reported as the baseline sum diameters. This will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease.

Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must 
have a reduction in short axis to < 10 mm. Changes in tumor measurements must be 
confirmed by repeat studies performed no less than 6 weeks after the criteria for 
response are first met.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. Changes in tumor 
measurements must be confirmed by repeat studies performed no less than 6 weeks 
after the criteria for response are first met.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as references 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. The appearance of one or 
more new lesions is also considered progression.

Stable Disease (SD): Neither a sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameter while on 
study. Participants having a documented response with no confirmation of the response 
will be listed with stable disease.
Non-Target Lesions
All other small lesions (longest diameter < 10 mm or lymph nodes ≥ 10 mm to < 15 mm short 
axis) and non-measurable lesions (i.e., leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, blastic bone 
lesions, or abdominal masses / abdominal organomegaly identified by physical exam that is not 
measurable by imaging) should be identified as non-target lesions and indicated as present in the 
source documents at baseline. The general location will also be documented on the images drawing 
a regularly-shaped Region of Interest. Measurements of the non-target lesions will not be 
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performed, but the presence or absence of each should be noted throughout follow-up and 
evaluation.
Complete Response: Disappearance of all non-target lesions and normalization of tumor marker 
level, if applicable. All lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-Complete Response/Non-Progressive Disease: Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the upper limits of normal.
Progressive Disease: Appearance of 1 or more new lesions or the unequivocal progression of 
existing non-target lesions. Although a clear progression of non-target lesions is exceptional, in 
such circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed at a later time.
Evaluation of Response
Time point response assessments will be performed every 12 weeks [starting with Week 12 ± 1 
week)]. To determine time point response, refer to the tables below:
Time Point Response Criteria: 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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Time Point Response Criteria: non-target disease only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD1
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
1
Non-CR/non-PD is preferred over SD for non-target disease since SD is used as endpoint 
for assessment of efficacy in trials so to assign this category when no lesions can be 
measured is not advised.
The best overall response is the best response recorded from the start of study treatment until 
disease progression, taking into account any requirement for confirmation. In general, the 
participant’s best response assignment will depend on the achievement of both measurement and 
confirmation criteria and will be determined by combining the participant’s status of target lesions, 
non-target lesions, and new lesions.

Symptomatic Deterioration: Participants with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 
progression at that time, and not related to study treatment or other medical conditions 
should be reported as progressive disease due to “symptomatic deterioration.” Every 
effort should be made to document objective progression even after discontinuation of 
treatment due to symptomatic deterioration. Symptomatic deterioration that may lead 
to discontinuation of treatment include, but is not limited to, symptoms such as:

Weight loss > 10% of body weight.

Worsening of disease-related symptoms (e.g., worsening dyspnea, increasing 
pain/increasing requirement for narcotic analgesics).

Decline in performance status of > 1 level on ECOG scale.
Confirmation Measurement
If Week 12 CT scan demonstrates stable disease/response, patients will continue in follow-up with 
CT imaging every 12 weeks until progression, clinical deterioration or withdrawal from study.
Methods of Measurement
Refer to protocol Section 16.2
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Appendix G
Immune-Related Response Criteria (iRECIST)
Tumor response will be assessed using the Immune-Related response Criteria (iRESIST) as 
described by Seymour et al, 2017(20)*.
iRECIST Response Assessment
Overall response will also be assessed using iRECIST. Immunotherapeutics may result in 
infiltration of immune cells leading to transient increase in the size in malignant lesions, or 
undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 in 
many respects but have been adapted to account for instances where an increase in tumour burden, 
or the appearance of new lesions, does not reflect true tumour progression.
Key differences are described below. All responses defined using iRECIST criteria are designated 
with a prefix. iRECIST time-point and best overall responses will be recorded separately.
Confirming Progression
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms iUPD 
(unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans should be 
performed at least 4 weeks, but no longer than 8 weeks after iUPD.
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is seen 
as evidenced by one or more of the following:

Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions
o
Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum
o
Continued unequivocal progression in non-target disease with an increase in 
tumour burden 
o
Increase in size of previously identified new lesion (s) (an increase of at least 5 mm 
in the absolute value of the sum of those considered to be target new lesions) or 
additional new lesions.

RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions.
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are met 
compared to baseline). As can be seen in table 2, the prior documentation of iUPD does not 
preclude assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall 
response (BOR) providing that iCPD is not documented at the next assessment after iUPD.
New lesions
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum 
of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short axis for nodal 
lesions), and recorded as New Lesions-Target (NLT) and New Lesion-Non-Target (NLNT) to 
allow clear differentiation from baseline target and non-target lesions.
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New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 
measurements of target lesions should NOT be included in the sum of measures of original target 
lesions identified at baseline. Rather, these measurements will be collected on a separate table in 
the case record form.
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 
weeks (but not more than 8 weeks) after iUPD confirms further progression from iUPD with either 
an increase of at least 5 mm in the absolute value of the sum of NLT OR an increase (but not 
necessarily unequivocal increase) in the size of NLNT lesions OR the appearance of additional 
new lesions.
The following tables describe the time-point response (Table A) and best overall response (Table 
B) assessment when using iRECIST.
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Table A: Time-point (TP) iResponse
Time Point Response
Target 
Lesions*
Non-
Target 
Lesions*
New 
Lesions* No 
prior 
iUPD*
Prior iUPD**; ***
iCR
iCR
No
iCR
iCR
iCR
Non-
iCR/Non- 
No
iPR
iPR
iPR
Non-
iCR/Non- 
No
iPR
iPR
iSD
Non-
iCR/Non- 
No
iSD
iSD
iUPD with 
no change 
OR
decrease 
from
las
iUPD 
with 
no 
change
O
R decrease from 
last TP
Yes
NA
NLs confirms iCPD if NLs were previously identified and 
increase in size (≥5 mm in SOM for NLT or any increase 
for NLNT) or number. If no change in NLs (size or number) 
from last TP, remains iUPD
iSD
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based in further increase 
in size of NT disease (need not meet RECIST 1.1 criteria 
for unequivocal PD)
iUPD
Non-
iCR/Non- 
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based on:
o further increase in SOM of at least 5 mm, otherwise 
remains iUPD
iUPD
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based on further 
increase in:
o previously identified T lesion iUPD SOM ≥5 mm and / or
o NT lesion iUPD (prior assessment - need not be 
unequivocal PD)
iUPD
iUPD
Yes
iUPD
Remains iUPD unless iCPD confirmed based on further 
increase in:
o previously identified T lesion iUPD ≥5 mm and / or
o previously   identified   NT   lesion   iUPD   (need   not   
be unequivocal) and /or
o size or number of new lesions previously identified
Non- 
iUPD/PD
Non-iUPD/PD
Yes
iUPD
Remains iUPD unless iCPD confirmed based on
o increase in size or number of new lesions previously 
identified
* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD 
would be the same. ** in any lesion category. *** previously identified in assessment immediately prior to this TP.
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All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below.
Table B: iRECIST Best Overall Response (iBOR)
TPR1
TPR2
TPR3
TPR4
TPR5
iBOR
iCR
iCR,
iP
iCR, iPR, iUPD, 
NE
iUPD
iCPD
iCR
iUPD
iPR, iSD, NE iCR
iCR, iPR, iSD, iUPD, NE
iCR, iPR, iSD, iUPD, iCPD, NE iCR
iUPD
iPR
iPR, iSD, iUPD, NE iPR, iSD, iUPD, NE, 
iPR, iSD, iUPD, NE, iCPD
iPR
iUPD
iSD, NE
PR
iPR, iSD, iUPD, NE
iPR, iSD, iUPD, iCPD, NE
iPR
iUPD
iSD
iSD, iUPD, NE
iSD, iUPD, iCPD, NE
iSD, iUPD, ICPD, NE
iSD
iUPD
iCPD
Anything
Anything
Anything
iCPD
iUPD
iUPD
iCPD
Anything
Anything
iCPD
iUPD
NE
NE
NE
NE
iUPD

Table assumes a randomized study where confirmation of CR or PR is not required.

NE = not evaluable that cycle.

Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation.

For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each TPR 
but is not shown in the table for ease of presentation.
Methods of Measurement
Refer to protocol Section 16.2.
* For additional information, refer to the following article and online supplemental information:
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey 
J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella 
C, de Vries EG, group Rw. iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e52. doi: 10.1016/S1470-2045(17)30074-8. 
PubMed PMID: 28271869.
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Appendix H
Celecoxib Patient Diary
Protocol # __________________
                
     Patient Name:  ______________
Drug Name: Celecoxib
     
     Med. Record #: ___ ___ ___ ___ ___ ___
Study Medication Calendar
You are participating in a study that requires Celecoxib 200 mg to be given twice daily, 
approximately 12 hours apart on certain days. Your morning dose of Celecoxib will be given to 
you along with your pre-medications while you are in clinic. Please complete this calendar to 
document your evening doses of Celecoxib. Your nurse will let you know what time you receive 
your morning dose of Celecoxib so you can take your evening dose approximately 12 hours after.
Cycle # #______:
Date
Time that morning 
dose was taken (to be 
completed by the 
nurse in clinic)
Evening Dose
Time
Patient’s Initials
Please remember to bring this calendar and your pill bottle (including any unused pills) with you 
to your next study appointment.
______________________________________________________________________________________
Coordinator use only
Date of return: __________________
# of pills
(dispensed: _______     --   returned: _______)
       
_____________________________________     x   100   =    % adherence: __________
    
 # of pills scheduled _______        
 
______________________________________________________________________________________
Patient signature: _________________________________________                           Date: ____________
Investigator signature: _____________________________________                           Date: ____________
                                                                                                                  
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Appendix I
Schedule of Procedures and Observations
Post-Treatment Follow-Up
Evaluation
Screening/ 
Baseline1
Within 2 
weeks 
(± 3 days) 
prior to 
Cycle 1
Cycle 1
Days 1-3
(Week 1)
Cycles 2-4
Days 1-3 
(Weeks 4, 
7, 10)
Treatment 
Discontinuation
(± 3 days)
Week 122
(±1 week)
SafetyFollow-
Up3
Follow-
Up at 3 
and 6 
months
Long 
Term 
Follow-
Up
Medical History
X11
Physical 
Examination 
(including height 
and weight)4
X
X
X
X
X
Vital signs5
X
X
X
X
X
ECOG 
Performance 
Status
X
X
(Day 1
 only)
X
(Day 1only 
of each 
cycle)
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
Survival Status
X
X
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Post-Treatment Follow-Up
Evaluation
Screening/ 
Baseline1
Within 2 
weeks 
(± 3 days) 
prior to 
Cycle 1
Cycle 1
Days 1-3
(Week 1)
Cycles 2-4
Days 1-3 
(Weeks 4, 
7, 10)
Treatment 
Discontinuation
(± 3 days)
Week 122
(±1 week)
SafetyFollow-
Up3
Follow-
Up at 3 
and 6 
months
Long 
Term 
Follow-
Up
Laboratory 
Procedures
Infectious 
Disease Panel 
(HBV and HCV)
X
Hematology6
X
X6a
X6a
X
X
Chemistry7
X
X7a
X7a
X
X
TSH, T414
X
X14a
X14b
HLA-A2 typing 
(confirmation of 
HLA 
eligibility)15
X
Urine βHCG 
pregnancy test8
X

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Post-Treatment Follow-Up
Evaluation
Screening/ 
Baseline1
Within 2 
weeks 
(± 3 days) 
prior to 
Cycle 1
Cycle 1
Days 1-3
(Week 1)
Cycles 2-4
Days 1-3 
(Weeks 4, 
7, 10)
Treatment 
Discontinuation
(± 3 days)
Week 122
(±1 week)
SafetyFollow-
Up3
Follow-
Up at 3 
and 6 
months
Long 
Term 
Follow-
Up
Troponin I level9
X
Leukapheresis10
X
Blood Draw for 
Correlative 
Analysis12
X12a
X12a
X
X
Imaging / Other 
Procedures
12-lead EKG9
X
Tumor/Disease 
Assessment (CT 
scan of the chest 
abdomen and 
pelvis)11
X
X11a
X11a
X11a
Biopsy13
X
X
Treatment 
Regimen 
Administration

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Post-Treatment Follow-Up
Evaluation
Screening/ 
Baseline1
Within 2 
weeks 
(± 3 days) 
prior to 
Cycle 1
Cycle 1
Days 1-3
(Week 1)
Cycles 2-4
Days 1-3 
(Weeks 4, 
7, 10)
Treatment 
Discontinuation
(± 3 days)
Week 122
(±1 week)
SafetyFollow-
Up3
Follow-
Up at 3 
and 6 
months
Long 
Term 
Follow-
Up
Chemokine 
modulation 
(CKM)
X
X
αDC1/TBVA 
cell-based 
injection16
X
Footnotes
1.
Baseline and/or Screening assessments must be performed within 28 days prior to the first cycle of the CKM treatment 
regimen.
2.
Week 12: Response rate will be evaluated by CT scan, performed as a part of standard care at week 12 (± 1 wk). Any patient 
with PD will be offered an opportunity to switch to the best alternative treatment, per physician discretion [(e.g., LAG-3 
(OPDUALAG™) or CTLA4 blockade (Ipilimumab) ± PD-1/PD-L1 inhibitor (unless contra-indicated)] and will be assessed as 
per standard of care guidelines. Any patient with a CR, PR or SD will be offered PD-1/PD-L1 blockade (according to the 
approved standard of care regimen) or best alternative care (per physician discretion). Thereafter, patients will be contacted by 
phone every 3 months for up to 2 years by medical record review/telephone call for survival status and other anti-cancer 
therapies.
3.
To capture all possible delayed immune-related adverse events, follow-up safety evaluations will occur at least monthly for 
90 days after last dose of study drug or until resolution of any drug-related toxicity (medical record review or telephone contact 
is acceptable).
3a: Patients will be contacted by phone every 3 months up to 2 years by medical record review/telephone call for survival 
status and other anti-cancer therapies.

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4.
Physical exam to include assessment of Head/Ears/Eyes/Nose/Throat (HEENT), Skin, Chest/Lungs, Heart, Neck/Lymph 
nodes, Abdomen, Extremities and weight. Height required at baseline only.
5.
Vital Signs include blood pressure, pulse, temperature and respiratory rate. On days that rintatolimod is given, vital signs will 
be obtained pre-treatment, 30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) post rintatolimod. Following the αDC1 
vaccination patients will be monitored as outpatients (every 20 min ± 5 min) for 1 hour. Monitoring will consist of vital sign 
measurements, and monitoring of any local/systemic reactions to the injection. This monitoring will include clinical 
assessment of pain, tenderness, warmth and swelling.
6.
CBC with automated differential
6a: Labs are ONLY taken once per cycle: Day 1 of each cycle unless otherwise clinically indicated.
7.
CMP
7a: Only Day 1 of each cycle unless otherwise clinically indicated.
8.
Within 7 days of Day 0 in women of child-bearing potential (and as clinically indicated once on treatment).
9.
A single 12-lead ECG and Troponin I level to be performed at screening and then only as clinically indicated thereafter.
10. Patient MUST meet inclusion/exclusion criteria prior to leukapheresis. Leukapheresis to occur approximately 2 weeks prior to 
Cycle 1-Day 1 (first CKM treatment regimen). It is expected that 1 leukapheresis will yield enough cells for at least 3 i. d. 
αDC1 cell-based injections. If a sufficient number of cells have not been obtained, an additional leukapheresis may be required 
in order to complete the treatment protocol. If a sufficient number of cells for 3 i. d. αDC1 cell-based injections and proposed 
QC testing are still not obtained after the second leukapheresis, the patient will be withdrawn from the study and replaced. 
11. Baseline disease assessment may be within 28 days prior to Day 0.
11a: If Week 12 CT scan demonstrates stable disease/response, patients will continue in follow-up with CT imaging every 
12 weeks until progression, clinical deterioration or withdrawal from study. Any patient with PD will be offered an opportunity 
to switch to CTLA4 blockade (Ipilimumab) ± PD-1/PD-L1 inhibitor and will be assessed as per standard of care guidelines.
12. ONLY Day 1 and Day 3: Refer to Section 0.
12a: Day 1 and Day 3 of Cycles 1, 2, 3 and 4: Pre-infusion and at 1 hr (± 10 minutes) post-rintatolimod infusion
13. Refer to Section 0: Fresh Biopsy Specimens.
14. Thyroid: TSH and T4 (only twice per protocol):
14a: Cycle 1 Day 1 only
14b: Cycle 3 Day 1 only

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15. Participant must sign a separate informed consent prior to HLA testing. HLA-A2 positivity is required for study eligibility. 
Samples for HLA-A2 typing for eligibility will performed by a CLIA certified laboratory, as selected by site.
16. The αDC1 cell-based injection is administered only on Day 1 of Cycles 2-4 (1 hr +30 min/-15 min) prior to initiating CKM 
pre-treatment.