Phase I/II Study of Low-Dose Cyclophosphamide, Tumor Associated Peptide Antigen-Pulsed Dendritic Cell Therapy and Imiquimod, in Patients With Progressive and/or Refractory Solid Malignancies
Phase: PHASE1
Conditions: Progressive Solid Malignancies, Refractory Solid Malignancies, Cancer
Sponsor: Kiromic BioPharma Inc.

 
 
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Phase I/II Study of Low Dose Cyclophosphamide, Tumor Associated Peptide 
Antigen-Pulsed Dendritic Cell Therapy and Imiquimod, in patients with 
Progressive and/or Refractory Solid Malignancies. 
 
 
 
Protocol Number:  
KIROVAX-003 
 
Date:   
 
August 22, 2018 
 
Version:  
  
007  
 
 
 
IND Number:  
12612 
 
 
 
 
 
 
 
 
 
Sponsor:  
 
Kiromic, Inc 
7707 Fannin Street, Suite 140 
Houston, TX  77054 USA 
Phone: (832) 968-4888 
Fax: (866) 419-6193 
 
 
 
 
 
 
 
Confidentiality Statement 
 
This document and the information contained herein or attached hereto (“Confidential Material”) is confidential and 
proprietary to Kiromic (Polaris). The Confidential Material should only be viewed by those individuals or 
companies that have been given prior authorization to do so by Kiromic (“Authorized Users”). The Confidential 
Material should not be made available in any form to any person or company, other than the Authorized User and 
their respective employees or associates on a need-to-know basis, without the prior written consent from Kiromic. 
 

 
 
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Kiromic Signature Page 
 
 
 
 
 
Signature of Kiromic Study Chair 
 
dd mmm yyyy 
Scott Dahlbeck, MD, PharmD, Chief Medical Officer 
Printed Name of Kiromic Study Chair and Title 
 
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
 
 
 
22 Aug 2018

 
 
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Principal Investigator Signature Page 
 
 
 
 
 
Signature of Site Principal Investigator 
 
dd mmm yyyy 
 
 
Printed Name of Site Principal Investigator 
Institution Name: _______________________________________ 
By my signature, I agree to personally supervise the conduct of this study at my 
study site and to ensure its conduct is in compliance with the protocol, informed 
consent, Institutional Review Board (IRB)/Ethics Committee (EC) procedures, the 
Declaration of Helsinki, ICH Good Clinical Practices Guidelines, and local 
regulations governing the conduct of clinical studies. 
 
 
 
 

 
 
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TABLE OF CONTENTS 
ABSTRACT ................................................................................................................................................... 7 
1.0 
BACKGROUND AND SIGNIFICANCE ................................................................................................... 8 
2.0 
HYPOTHESIS AND OBJECTIVES ........................................................................................................ 15 
2.1 
Hypothesis ................................................................................................................................... 15 
2.2 
Primary Objective: Phase I .......................................................................................................... 15 
2.3 
Secondary Objectives: Phase II ................................................................................................... 15 
3.0 
STUDY DESIGN................................................................................................................................. 15 
3.1 
Study Population ......................................................................................................................... 15 
3.1.1 
Number and Characteristics of Patients Enrolled .............................................................. 15 
3.2 
Eligibility Criteria ......................................................................................................................... 16 
3.2.1 
Inclusion Criteria ................................................................................................................ 16 
3.2.2 
Exclusion Criteria ............................................................................................................... 17 
3.3 
Withdrawal Criteria ..................................................................................................................... 18 
3.3.1 
Reasons for Withdrawal of Patients from Study ................................................................. 18 
3.3.2 
Follow-up of Withdrawn Patients ........................................................................................... 18 
3.4 
Patient Replacement ................................................................................................................... 18 
3.4.1 
Reasons for Replacement .................................................................................................... 18 
3.5 
Study Schedule ............................................................................................................................ 19 
3.5.1 
Summary of Pre-treatment Evaluations .............................................................................. 19 
3.5.2 
Summary of Treatment Visits and Procedures .................................................................... 19 
3.6 
Safety Endpoints ......................................................................................................................... 20 
3.6.1 
Rules Based on Dose Limiting Toxicity .............................................................................. 20 
3.6.2 
Definition of Adverse Event and Adverse Reaction ............................................................ 20 
3.6.3 
Causality ............................................................................................................................. 20 
3.6.4 
Recording of Adverse Events (AE) ...................................................................................... 22 
3.6.5 
Follow-up of Adverse Events .............................................................................................. 23 
3.6.6 
Adverse Event Monitoring .................................................................................................. 23 
3.6.7 
Definition of Dose-Limiting Toxicity (DLT) ....................................................................... 23 
3.7 
Immune Efficacy Endpoint .......................................................................................................... 24 
3.7.1 
Immune Efficacy (IE) Rules ................................................................................................ 24 
3.8 
Reasons for Discontinuation of Study ......................................................................................... 25 
3.9 
Potential Risks and Benefits ........................................................................................................ 25 

 
 
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3.9.1 
Known Toxicities Associated with DC Vaccination............................................................... 25 
4.0 
METHODS AND ASSESSMENTS ....................................................................................................... 26 
4.1 
Contraception and Pregnancy Testing ............................................................................................ 26 
4.2 
Screening, Study Visits and Procedures........................................................................................... 26 
4.2.1 
Screening Visits and Procedures ................................................................................................ 26 
4.2.2 
Study Visits and Procedures ................................................................................................... 27 
4.2.3 
Final Study Visit .................................................................................................................. 29 
4.2.4 
Post-Study Follow-up .......................................................................................................... 29 
4.2.5 
 Discontinuation Visit.......................................................................................................... 30 
5.0 
STUDY MATERIALS AND PROCEDURES ........................................................................................... 30 
5.1 
Products........................................................................................................................................... 30 
5.1.1 
TAPA-Pulsed Dendritic Cells (DCs) ........................................................................................... 30 
5.2 
Storage and Drug Accountability ................................................................................................ 31 
5.2.1 
TAPA-Pulsed Dendritic Cells (DCs) ...................................................................................... 31 
6.0 
TREATMENT .................................................................................................................................... 31 
6.1 
Selection of TAPA-Pulsed DC Dose Level ......................................................................................... 31 
6.1.1 
Rationale ..................................................................................................................................... 31 
6.1.2 
TAPA-Pulsed DC Vaccination ............................................................................................ 31 
DCs per Vaccination ............................................................................................................................. 32 
6.1.3. 
Imiquimod Treatment .......................................................................................................... 32 
6.2 
Study Drug Administration .......................................................................................................... 32 
6.2.1 
Cyclophosphamide (CYP) ........................................................................................................ 32 
6.2.2  
TAPA-Pulsed Dendritic Cells (DC) .................................................................................... 32 
6.3 
Study Drug Quality and Safety Measures ................................................................................... 33 
6.3.1 
TAPA-Pulsed Dendritic Cells (DCs) ...................................................................................... 33 
6.4 
Specific Restrictions and Requirements...................................................................................... 33 
6.4.2 
Compliance with Therapy ................................................................................................... 34 
7.0 
SAMPLE SIZE AND STATISTICAL METHODS ..................................................................................... 34 
7.1 
Determination of Sample Size ......................................................................................................... 34 
7.1.1 
Sample Size for Safety Evaluation .............................................................................................. 34 
7.1.2 
Sample Size for Evaluation of Immune Efficacy ................................................................. 34 
7.2 
Statistical Methods ................................................................................................................. 34 
7.2.1  
Safety and Toxicity .............................................................................................................. 34 

 
 
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7.2.2 
Immune Efficacy (IE) .......................................................................................................... 34 
8.0 
ETHICAL CONSIDERATIONS ............................................................................................................. 35 
8.1 
Protection of Patients from Unnecessary Harm .............................................................................. 35 
8.2 
Privacy and Confidentiality ......................................................................................................... 35 
8.3 
Informed Consent ....................................................................................................................... 35 
8.4 
IRB Approval ................................................................................................................................ 35 
9.0 
SAFETY CONSIDERATIONS ............................................................................................................... 36 
9.1 
TAPA-Pulsed DC Vaccination ........................................................................................................... 36 
9.2 
Adverse Immune Responses Against TAPA-Pulsed DC Vaccinations .......................................... 36 
9.3 
Regulatory Aspects ..................................................................................................................... 36 
10.0 
FINANCIAL CONSIDERATIONS ......................................................................................................... 36 
11.0 
POTENTIAL CONFLICT OF INTEREST ................................................................................................ 36 
12.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................................................. 37 
13.0 
PUBLICATION POLICY ...................................................................................................................... 37 
14.0 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS, DATA HANDLING, AND RECORD KEEPING 
AND RETENTION OF STUDY DOCUMENTS .................................................................................................. 37 
APPENDIX 1: STUDY CALENDAR ................................................................................................................... 38 
APPENDIX 2: KARNOFSKY PERFORMANCE STATUS SCALE.......................................................................... 39 
APPENDIX 3: RESPONSE CRITERIA ............................................................................................................... 40 
APPENDIX 4: NCI CTCAE V4.0 ...................................................................................................................... 42 
APPENDIX 5: ADVERSE EVENT LOG .............................................................................................................. 43 
15.0 
REFERENCES .................................................................................................................................... 44 
 
 
 

 
 
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ABSTRACT  
Patients diagnosed with progressive and/or refractory solid malignancies (SM), who have 
failed conventional therapy, and have no available, potentially curative therapeutic options, 
will be candidates for this Phase I/II study.  Following confirmation of disease progression 
and/or refractoriness, eligible patients who agree to participate and sign a consent form will 
have their tumor cells/tissues and/or blood analyzed for the expression of a specific panel 
of Tumor Associated Peptide Antigens (TAPAs), including Sp17, ropporin, AKAP-4, 
PTTG1, Span-xb, Her-2/neu, HM1.24, NY-ESO-1 and MAGE-1.  Patients whose tumors 
express one (1) or more of these TAPAs will undergo phlebotomy and/or leukapheresis 
performed for generation of autologous DCs.  Patient’s DCs will be generated in Kiromic’s 
Cell Processing GMP facility, according to established Standard Operating Procedures, and 
activated by pulsing/loading them with the TAPA(s) relevant for each particular patient.  
Patients will receive five (5) days of low-dose cyclophosphamide prior to each vaccination 
with TAPA-pulsed DCs to decrease Treg activity. TAPA-pulsed DCs will be administered 
at a fixed dose of up to 1 X 107 DCs following cyclophosphamide administration.  DC 
vaccination schedule will be once every seven (7) days via intradermal (ID) injections for 
a total of 3 vaccinations.  Topical Imiquimod will also be administered once after the 
TAPA-pulsed DC vaccination, to optimize immune responses.  Patients will be followed 
on a weekly basis (or more frequently if required) to evaluate treatment-related toxicity.  
Immune efficacy and anti-tumor responses will be evaluated per protocol specifications.  
Continuation and stopping rules for the study will be defined based on toxicity/tolerability 
(Phase I) and immune efficacy (Phase II).  
 
 

 
 
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1.0 BACKGROUND AND SIGNIFICANCE  
Despite advances in understanding the biology of solid malignancies (SM), and the 
availability of new treatment options, the vast majority of patients with SM remain 
incurable (1). This is especially true for elderly patients and those whose disease proves 
refractory and/or relapses following standard therapy.  Therefore, therapeutic options for 
this patient population are quite limited and novel strategies are desperately needed for 
patients with progressive and/or refractory SM.  
Immunotherapy has recently emerged as a promising treatment strategy for patients with 
SM (2).  Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) and are 
necessary for the efficient priming and activation of naïve T-cells against specific antigens.  
DCs undergo maturation and activation in the presence of specific immunogenic antigens 
and serve as a critical link between innate and adaptive immunity resulting in antitumor 
responses (3).  It is now possible to generate human DCs in-vitro from monocytes exposed 
to GM-CSF and IL-4, and DC-based treatments have become one of the most attractive 
immunotherapeutic strategies for cancer in the last decade.  Indeed, DC vaccination studies 
have been conducted in several different neoplasms (4, 5) with variable results.    
Since most patients with progressive SM display a defective immune response to tumor 
antigens, the ex-vivo activation of DCs, through their exposure to tumor associated 
antigens, is an attractive and active area of investigation (6, 7).  A variety of early clinical 
studies have demonstrated the feasibility and promise of using antigen-pulsed DC therapy 
in patients with SM malignancies including metastatic prostate, hepatocellular, colorectal, 
renal, cervical, and breast carcinomas, as well as melanomas and glioblastomas (8-13).  
The fundamental strategies tested have included pulsing DCs with whole tumor cell lysates 
or specific tumor-associated antigens (8-13).  Although safe, DC vaccination strategies 
have resulted in unsatisfactory clinical outcomes attributed to either the poor 
immunogenicity of the target antigens, suboptimal DC-dosing, generation of tolerogenic 
DC subtypes and activity of suppressor regulatory T-cells (Treg).  Thus, results of these 
preliminary clinical studies indicate the need to optimize DC-based immunotherapy to 
improve responses in patients with SM. 
DCs can be safely generated from blood-derived monocytes in the presence of GM-CSF 
and IL-4 and administered safely to cancer patients (14, 15).  Moreover, DCs pulsed with 
specific Tumor Associated Peptide Antigens (TAPAs) are capable of eliciting immune and 
antitumor responses, without prohibitive toxicity (8-13, 16, 17).  Despite these advances 
many questions remain on how to improve this immunotherapeutic strategy, including how 
to best activate DCs with various antigens and cytokine combinations, the characterization 
of “ideal” TAPAs capable of eliciting strong and durable immune responses in patients 
with SM, the best vaccine immune adjuvants, the optimal dosing and schedule of DC 
treatments, how to inhibit inhibitory signals from Tregs and what specific group of patients 
with SM are best suited for this particular DC-based vaccination approach.  To solve these 
problems several potential strategies have been proposed including the use of more potent 
and immunogenic TAPAs and/or Th1 polarizing cytokines (18, 19), enhancement ex-vivo 

 
 
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DC maturation and activation through Toll-like receptor (TLR) signaling (20), cross 
presentation of neoplastic cell-associated antigens (21), stimulation of natural killer cell 
and/or T-helper activity to generate Th1 polarization in DCs (22), inhibition of 
immunosuppressive Treg cell populations (23) and regulation of DC migration to regional 
lymph nodes (24), among others.   
We and others have explored several potential TAPAs as immunotherapeutic targets in 
different malignancies.  These highly immunogenic proteins include Sp17, Ropporin, 
AKAP-4, PTTG1, Span-xb, Her-2/neu, HM1.24, NY-ESO-1, MAGE-1, and are thought to 
be potential targets for DC-based immunotherapy based on the following observations: 
Sperm protein 17 (Sp17)  
Sp17 is a highly immunogenic spermatozoan protein which has been considered a potential 
therapeutic target for immunocontraception in the last few years (25).  We have identified 
Sp17 as a novel Cancer-Testis Antigen (CTA) in hematologic and SM.  Using RT-PCR, 
Sp17 transcripts were detected in more than 70% of tumor-cell enriched bone marrow from 
multiple myeloma (MM) patients.  Sp17 gene expression was associated with Sp17 protein 
translation as demonstrated by Western blot analysis.  Importantly, Northern blot analysis 
and RT-PCR, demonstrated Sp17 expression in normal testis and tumor cells, but not in 
normal tissues, suggesting Sp17 could serve as an excellent immunotherapeutic target in 
MM (26). We have cloned the full-length coding sequence of the Sp17 cDNA and 
successfully generated Sp17-specific HLA-class I restricted cytotoxic T lymphocyte (CTL) 
after “pulsing” monocyte-derived DCs with the E. coli-derived recombinant Sp17 protein 
(14). These Sp17-specific CTLs were able to lyse autologous target cells pulsed with 
recombinant Sp17 protein as well as Sp17-expressing fresh MM cells.  Moreover, we have 
generated a synthetic Sp17 peptide (103-111) (ILDSSEEDK) capable of inducing HLA-
A1 restricted CTL recognition and activation (27).  We have also expanded our evaluation 
of Sp17 potential as an immunotherapeutic target by recently demonstrating its strong 
immunogenicity in an ovarian cancer animal model (28) and have recently found Sp17 is 
expressed in human lung cancer cell lines and tumor tissues, but not in normal lung (29). 
More importantly, we have shown Sp17-loaded DCs activate CTLs capable of eliciting 
antitumor responses, in vitro (29).  Finally, Dadabayev et al have reported the safety and 
clinical response of Sp17-pulsed DCs in patients with MM and ovarian cancer, validating 
the clinical potential of this protein as an immunotherapeutic target (30).  Taken together, 
these findings suggest the feasibility of exploiting Sp17-pulsed DC immunotherapy as a 
promising treatment option for patients with both hematologic and SM.  
AKAP-4 
A-kinase anchoring protein 4 (AKAP-4) is a member of a growing family of scaffolding 
proteins involved in the control of signal transduction by targeting cyclic adenosine 
monophosphate-dependent protein kinase-A, and directing its actions (31, 32). We have 
shown that AKAP-4 is expressed in lung cancer and MM cells, at both the transcriptional 

 
 
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and the protein level, with no evidence of expression in human normal tissues, other than 
the testis (29, 33).  The lack of expression in normal tissues and the presence of AKAP-4 
antibodies in lung cancer and MM patient sera supports the protein’s immunogenicity and 
indicates AKAP-4 is a novel TAPA in these two malignancies.  Additionally, we have also 
demonstrated AKAP-4 serves as a marker of disease status in a murine model of MM, 
supporting its importance in the biology of this disease (34).  Thus, our findings suggest 
AKAP-4 is a potential target for developing specific immunotherapeutic strategies against 
MM, lung cancer and possibly other SM (29).    
Ropporin 
Ropporin is a rhophilin-associated protein normally expressed in the inner fibrous sheath 
of sperm flagella.  Ropporin has previously been found to interact with other fibrous sheath 
proteins, including Sp17 and AKAP-110, suggesting a common or related biological 
function.  A study by Li et al has demonstrated a very restricted RNA expression of 
ropporin in normal tissues, with the exception of testicular and fetal liver tissue (35).  
Ropporin expression was also detected in tumor cells derived from the bone marrow in 6 
of 16 (37.5%) patients with MM, 6 of 14 (43%) cases of CLL and 2 of 11 (18%) cases of 
acute myeloid leukemia.  No ropporin transcripts were detected in the peripheral blood 
mononuclear cells of 17 healthy donors.  Importantly, these investigators detected high 
titers of antibodies against ropporin in 8 of 30 MM (26.7%), 7 of 24 AML (29.2%), 18 of 
31 chronic lymphocytic leukemia (CLL) (58.1%), 9 of 27 chronic myelogenous leukemia 
(CML) (33.3%) and 1 of 3 acute lymphoblastic leukemia (ALL) (33.3%), compared to 
healthy donors.  The presence of ropporin antibodies in patients with a variety of 
malignancies indicates this CTA is a highly immunogenic protein.  Taken together, these 
findings support the notion that ropporin is a tumor-restricted CTA with a potential role in 
the biology of certain neoplasms.  The restricted expression of ropporin in neoplastic cells, 
testes and fetal liver, makes it a suitable candidate as a target for immunotherapy including 
DC vaccine applications.  
PTTG-1 
PTTG-1 is a novel oncogene involved in transcriptional and cell cycle regulation with 
expression in the normal testis and thymus (36).  PTTG-1 has been shown to be highly 
expressed in different hematologic malignancies (HM) including promyelocytic leukemia 
(PML) cell line HL-60, CML cell line K-562, ALL cell line MOLT-4 and Burkitt's 
lymphoma cell line Raji (37).  PTTG-1 has also been shown to be associated with 
tumorigenesis, angiogenesis and cancer progression, making it a logical therapeutic target 
(36). We and others have found PTTG-1 is expressed at the transcriptional level in MM, 
with PTTG-1 being expressed in 63% of MM patients and 66% of human MM cell lines 
studied, but not in normal tissues (38). We also documented cytoplasmic and surface 
PTTG-1 expression in plasma cells from MM patients supporting PTTG-1 potential role 
as a therapeutic target in patients with HM.  More recently, we have also demonstrated 
PTTG-1 expression in lung cancer tissues and cell lines and showed PTTG-1-loaded DCs 

 
 
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can activate CTL-mediated lysis of human lung cancer cells, in vitro (29).  Therefore, our 
data indicates the suitability of using PTTG-1 as a potential target for immunotherapy in 
both HM and SD.       
Span-xb  
Span-xb is a novel CTA expressed in CML and other neoplasms.  Using RT-PCR, we have 
detected Span-xb transcripts in 20% of MM patients, 33% of patients with CLL, 29% of 
CML patients and 50% of patients with AML. In contrast, Span-xb expression was not 
detected in peripheral blood or bone marrow samples from healthy donors (39).  
Importantly, span-xb gene expression has also been found in a variety of SM, including 
melanoma and carcinomas of the lung, colon and breast, making it a target for 
immunotherapeutic interventions (40). 
Her-2/neu 
HER-2/neu is a trans-membrane tyrosine-kinase involved in aberrant signal transduction 
in a variety of neoplasms (41, 42).  HER-2/neu amplification has been demonstrated in 
certain HM and its functional inhibition, using anti-sense oligonucleotides, results in a 
reduced tumor cell proliferative rate.  The observation that Her-2/neu is expressed at very 
low levels in normal tissues and preferentially expressed in neoplastic cells, suggest it 
could serve as an immunotherapeutic target in HER-2/neu-expressing SM.  In fact, 
Scardino et al have demonstrated HLA-restricted CTL activation by high several high 
affinity HER-2/neu peptides capable of HLA-restricted killing of neoplastic cells of diverse 
origin (43). Thus, specific Her-2/neu peptides may serve as good candidates for 
immunotherapy in HER-2-expressing SM.     
HM1.24   
The HM1.24 protein is a novel, 29-33 kDa membrane glycoprotein expressed in mature B-
cells.  We have proposed HM1.24 as a new antigen for CTLs activation against MM (44).   
HM1.24 expression has been found in all five human MM cell lines assayed, as well as in 
mature, Ig-secreting B-cells (plasma cells and lymphoplasmacytoid cells), but not in non-
B-Cells in the peripheral blood, bone marrow, liver, spleen, kidney, or heart of normal 
individuals or patients with non-plasma-cell-related malignancies. Thus, HM1.24 protein 
represents a specific marker of late-stage B-cell maturation and may potentially serve as a 
target antigen for the development of immunotherapeutic strategies specific against MM.  
HM1.24 is also expressed in SM including brain tumors, renal, hepatocellular, breast, 
ovarian, and breast carcinomas, with some expression in a few normal organs including 
liver and kidney (45).  Although HM1.24 function is unknown at this time, its promise as 
a therapeutic target has been demonstrated using a specific HM1.24 monoclonal antibody 
(MoAb) (46). 
 

 
 
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NY-ESO-1 
NY-ESO-1 is one of the most immunogenic tumor antigens known to date. Spontaneous 
humoral and cellular immune responses against NY-ESO-1 are detected in a substantial 
proportion of patients with NY-ESO-1 expressing malignancies and NY-ESO-1 antibody 
titers correlate with clinical development of disease (47).  Moreover, the development of 
NY-ESO-1 serum antibody is associated with detectable NY-ESO-1-specific CD8+ T cell 
reactivity, suggesting this antigen is an excellent immunogen and potential therapeutic 
target, in vivo (48).  
MAGE-1  
MAGE-1 is expressed in hematologic malignancies, including human MM cell lines and 
malignant plasma cells, as well as melanomas (49, 50). Both RNA and protein expression 
has been demonstrated in MM cells, but not in polyclonal, reactive plasma cells. Moreover, 
anti-MAGE-1 HLA-A1 cytotoxic T lymphocytes can efficiently kill MAGE-1 HLA-A1 
expressing MM and melanoma cells, suggesting MAGE-1 represents a specific and 
potential immunotherapeutic target for patients with these malignancies. 
Using an HLA binding prediction algorithm, we have identified peptides, within the 
sequence of the above-mentioned antigens, predicted to have high binding affinity to HLA-
class I and class II molecules. Peptide sequences from each antigen were linked together 
using the furin-sensitive linker, RVKR. This linker is used to connect peptides with 
different HLA restrictions to form a unique long peptide, and it was shown to be safe and 
effective in previous clinical trials linking the MAGE-A3 or human papillomavirus (HPV)-
16 derived peptides, and the a “penetrin” peptide sequence derived from HIV-TAT  (51, 
52) (IND#10927, #NCT00257738). 
The rationale for using long peptides (synthetic long peptides, SLP) is based on the 
evidence that dendritic cells present SLP better than whole proteins, and that the anti-SLP 
immune repose lasts longer than that of short peptides (53, 54). 
The SLP sequences are as follows (the linker peptide, RVKR, is evidenced in bold). 
 
1) SP17 
SP17- peptide A IPQGFGNLLEGLTREILRVKRDNIPAFAAAYFESLLERVKRKTNFDPAEW 
SP17-peptide B KEEETSVTILDSSEEDKEKEEVAAVKIQAAFRGHIARRVKRAKKMKTNSL 
2) AKAP4 
AKAP4- peptide A 
MMAYSDTTMMSDDIDWLRVKRYALGFQHALSPSTSTRVKRYADQVNIDYLMNRPQNLRLEMRVKRCSID
DLSFYVNRLSSLVIQMA 
AKAP4- peptide B 
FLYSELSNKRVKRPASVVLKRVLLRHTKEIRVKRMEAMLKRLVSALIGERVKRQSLSYASLK 

 
 
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AKAP4- peptide C GEHILKEGLRVKRMSNIVLMLIRVKRWIAASQFNVPMLYRVKREAVGKVARK 
3) PTTG1 
PTTG1- peptide A KLGSGPSIKRVKRRSQVSTPRFRVKRLPKATRKALGTVNRATEK 
PTTG1- peptide B 
FFPFNPLDFRVKREHQIAHLPLRVKRRELEKLFQLGPPSPVKMRVKRILSTLDVELPPV 
4) ROPPORIN-1 
ROPN1- peptide A DLIQWAADYFEALRVKRLLKILHSQVAGRLIIRAEELAQMW 
ROPN1- peptide B IEWLKFLALACSALGVTITRVKRSPRIPFSTFQFLYTYIAKVDGEIRVKRHVSRMLNYM 
5) Spanx-B1 
SPNXB1 SESSTILVVRYRRNVKRTSRVKRMEEEEFIEI 
6) NY-ESO-1 
NYESO1- peptide A APRGPHGGARVKRRLLEFYLAMPFATPMRVKRSLAQDAPPL  
NYESO1- peptide B ILTIRLTAADHRQLQLSISSCLQQLSLLMWIRVKRFLPVFLAQPPSGQRR 
7) MAGE-1 
MAGE1- peptide A SAFPTTINFRVKRILESLFRAVITKKVADLVGFLRVKRIMPKTGFLI 
MAGE-1 peptide B EIWEELSVMRVKRAETSYVKVLEYVIKVSARVRFFFPSLREAAL 
8) Her2/Neu 
Her2/Neu peptide A 
CRWGLLLALRVKRHLDMLRHLYRVKRLELTYLPTNASLSFLRVKRQLFEDNYAL 
Her2/Neu peptide B 
ETLEEITGYRVKRSVFQNLQVIRGRILHRVKRRELGSGLALRVKRFRNPHQALLRVKRLTSIISAVVRVKRLIKRR
QQKIRKYTMRRLLQ 
Her2/Neu peptide C 
SGAFGTVYKRVKRVMAGVGSPYRVKRMQIAKGMSYRVKRGKVPIKWMALESILRRRFTRVKRSYGVTVWE
LRVKRAARPAGATLRVKRPAFDNLYYW 
9) HM1.24 
KRCKLLLGIRVKRPLIIFTIKANSEACRRVKRHTVMALMASLDAEKARVKRKLQDASAEVRVKRVLSVRIADK 
 
Being more specific, and potentially less toxic than chemotherapy, immunotherapeutic 
strategies, such as TAPA-pulsed DC vaccination, may prove an ideal treatment for patients 
with a variety of SM.  In fact, such an approach has recently gained FDA approval for 

 
 
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patients with advanced prostate cancer (55). Therefore, studies using novel TAPAs are 
clearly warranted in patients with limited therapeutic options, such as those with 
progressive and/or refractory SM.  
 
A promising way of optimizing the efficacy of therapeutic vaccines would be the inhibition 
of suppressive T-cell populations, such as Tregs.  It has been recognized for many years 
that cyclophosphamide (CYP) can exert both cytotoxic and immunosuppressive effects, 
depending on the dose used. For example, studies have shown that low-dose 
cyclophosphamide (CYP) decreases Treg number and functionality (56). Greten and 
colleagues evaluated single-agent CYP doses of 150, 250, and 350 mg/m2 in patients with 
hepatocellular carcinoma and reported that the two (2) lower doses induced a decrease in 
the absolute and relative frequency of Tregs in the blood of patients, and the 250 mg/m2 
dose impaired suppressor function and showed decreased Treg frequency up to day 71. 
Alpha-fetoprotein–specific T-cell responses were also induced in the lower treatment arms 
(57). In a different study, breast cancer patients received CYP, 50 mg orally daily for 3 
months.  Tregs were reduced within 14 days of treatment and remained decreased until day 
42, returning to pretreatment levels by day 84. Interestingly, endogenous breast tumor–
reactive T cells were detected in 27% of patients before CYP treatment and increased to 
73% on day 14, 80% on day 42, and 88% on day 84, indicating enhanced T-cell function 
after the use of metronomic doses of CYP (58).  More recently, the use of metronomic 
CYP combined with active immunotherapy has been reported (59).  In this study, patients 
with advanced solid tumors were treated with 3 different regimens of low-dose CYP in 
combination with an oncolytic adenovirus. CYP was given either as oral metronomic (50 
mg/day), a single intravenous (i.v.) injection (1,000 mg), or both. Metronomic CYP was 
given starting 1 week before the adenovirus, and i.v. cyclophosphamide was given 1 hour 
prior to the adenovirus.  All CYP regimens resulted in higher rates of disease control when 
compared with the rates for the adenovirus vaccine only, and the metronomic groups were 
most effective in decreasing Treg numbers. Based on these encouraging results numerous 
studies are in progress combining metronomic doses of CYP with active vaccination 
strategies (ClinicalTrials.gov) for a variety of cancers.  For an excellent discussion on the 
role of low-dose CYP as a suppressor of Treg activity and its potential in cancer 
immunotherapy, see the review by Le and Jaffee (60).   
 
Two additional strategies to optimize the efficacy of anti-tumor cellular vaccines would be 
to improve the ex-vivo generation of DCs with an immunogenic phenotype and to select 
appropriate adjuvant molecules or cytokines to enhance DC migration and activation, in 
vivo. For example, the use of type I interferons and Toll-like receptor agonists to induce 
DC maturation ex-vivo have been shown to stimulate generation of immunogenic, rather 
than tolerogenic, DCs (6, 61).  
Activation of Toll-Like Receptor 7 (TLR7) has been shown to improve the survival and 
immunogenicity of DC (62-64) (#NCT01792505). Additionally, topical usage of the 
imiquimod cream meaningfully improved DC migration and increased numbers of 
emigrated DCs. By contrast, intradermal injection of soluble imiquimod or the TLR7/8 

 
 
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ligand R848 did not result in the same effect  (65). Of note, TLR7 adjuvant is available as 
a topical cream, i.e. Imiquimod (Aldara cream), with evident advantages over other 
classical DC adjuvants such as GM-CSF, which requires injections (66).  
   
 
In this phase I/II study we will examine the feasibility, toxicity, immune response and 
antitumor activity of TAPA-pulsed DC therapy in patients with progressive and/or 
refractory SM.  To improve the efficacy of this strategy, selected TAPAs will be used to 
pulse DCs ex-vivo, in the presence of a highly immunogenic maturation cocktail (9, 12, 19, 
20).  Patients will also be treated with low-dose CYP prior to each DC vaccination, in an 
attempt to decrease the number and activity of Tregs, and topical Imiquimod will be 
administered following each DC vaccination, in order to optimize immune responses in 
patients with relapsed/refractory SM.  A similar strategy has recently been safely explored 
by others in patients with refractory SM (9).   
2.0 HYPOTHESIS AND OBJECTIVES  
2.1 
Hypothesis 
We hypothesize that treatment of patients with progressive and/or refractory SM, without 
available, potentially curative therapeutic options, and whose tumor cells express at least 
one (1) TAPA of a defined panel of TAPAs, using low-dose CYP followed by an 
autologous, monocyte-derived, TAPA-pulsed DC vaccine and topical Imiquimod, will 
result in TAPA-specific CD4+ T-cell and CD8+ CTL responses without significant 
toxicities.  We also hypothesize CD4+ T-cell and CD8+ CTL responses generated against 
specific TAPAs may translate into clinical antitumor activity. 
2.2 
Primary Objective: Phase I 
 
To determine the toxicity of low-dose CYP followed by TAPA-pulsed DC therapy and 
topical Imiquimod, in patients with progressive and/or refractory SM. 
2.3 
Secondary Objectives: Phase II  
 
To determine immune responses associated with low-dose CYP followed by TAPA-
pulsed DC therapy and topical Imiquimod, in patients with progressive and/or refractory 
SM. 
3.0 STUDY DESIGN 
3.1 
Study Population 
3.1.1 Number and Characteristics of Patients Enrolled 
1. 
The study population will be drawn from patients at various institutions in USA 
following contractual agreements with Kiromic. 

 
 
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2. 
There will be no patient restrictions based on race or gender. 
3. 
Up to six (6) subjects may be enrolled and receive DC vaccination to evaluate 
toxicity of the proposed vaccination strategy (Phase I stage).   
4. 
Up to an additional eleven (11) patients, for a total of seventeen (17) patients, may 
be enrolled for determination of immune efficacy (Phase II stage), assuming no 
overt toxicity is encountered during the safety evaluation.   
3.2 
Eligibility Criteria  
Patients must have baseline evaluations performed prior to administration of the first dose 
of study vaccine and must meet all inclusion and exclusion criteria.  In addition, the patient 
must be thoroughly informed about all aspects of the study, including the study visit 
schedule, required evaluations, and all regulatory requirements for informed consent.  The 
written informed consent must be obtained from the patient prior to enrollment.  The 
following criteria apply to all patients enrolled on the study unless otherwise specified. 
3.2.1 Inclusion Criteria 
1. 
Ability to provide informed consent. 
2. 
Patients with histologically proven progressive and/or refractory SM, s/p 
conventional salvage therapy, completed at least 3 weeks prior to study vaccination, 
will be eligible for enrollment. 
3. 
Expression of one (1) or more of the following TAPAs: Sp17, AKAP-4, Ropporin, 
PTTG-1, Span-xb, Her-2/neu, HM1.24, NY-ESO-1 and MAGE-1, by either RT-
PCR and/or immunocytochemistry, Western blotting or ELISA, in neoplastic cells.  
For HER-2/neu expression, positive FISH results are acceptable. 
4. 
Presence of measurable or evaluable disease. 
5. 
Patients must not have any active infectious process. 
6. 
Patients must not have a history of HIV, or active Hepatitis A, B, or C. 
7. 
Patients must not be receiving active immunosuppressive therapy.  
8. 
Patients must have discontinued systemic cytotoxic or radiation therapy at least 
three (3) weeks prior to vaccination and toxicities from previous therapies must be 
grade 1 or less.  All other FDA approved forms of antineoplastic therapy are 
allowed such as immunotherapy, targeted therapies, or hormonal therapies (67, 68). 
9. 
Patients may not have any known allergy to CYP and/or Imiquimod. 
10. 
Patients must be willing to provide at least 250 mL, and up to 500 mL, of whole 
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11. 
Adequate renal and hepatic function (creatinine ≤ 2.0 mg/dl, bilirubin ≤ 2.0 mg/dl, 
AST and ALT ≤ 4X upper limit of normal range). 
12. 
Adequate hematologic function (Platelets ≥ 60,000/mm3, lymphocytes ≥ 1,000 
mm3, neutrophils ≥ 750/mm3, hemoglobin ≥ 9.0 g/dl). 
13. 
Karnofsky performance status ≥ 70%. 
14. 
Expected survival ≥ 6 months. 
15. 
Either a female or male of reproductive capacity wishing to participate in this study 
must be using, or agree to use, one or more types of birth control during the entire 
study and for 3 months after completing the study.  Birth control methods may 
include condoms, diaphragms, birth control pills, spermicidal gels or foams, anti-
gonadotropin injections, intrauterine devices (IUD), surgical sterilization, or 
subcutaneous implants.  Another choice is for a subject’s sexual partner to use one 
of these birth control methods. Women of reproductive capacity will be required to 
undergo a urine pregnancy test before completion of the post-screening informed 
consent process. 
3.2.2 Exclusion Criteria 
1. 
Patients without confirmed progressive and/or refractory SM using standard 
RECIST criteria.  
2. 
Patients without measurable or evaluable disease. 
3. 
Patients receiving cytotoxic or radiation therapy, within three (3) weeks of 
vaccination. 
4. 
Active immunosuppressive therapy, including non-physiologic systemic steroids 
(excluding topical, intraocular, inhaled, and intranasal steroids) for any other 
condition. 
5. 
Persistent fever (>24 hours) documented by repeated measurement or active, 
uncontrolled infection within 4 weeks of enrollment. 
6. 
Active ischemic heart disease or history of myocardial infarction within six months. 
7. 
Active autoimmune disease, including, but not limited to, Systemic Lupus 
Erythematosus (SLE), Multiple Sclerosis (MS), Ankylosing Spondylitis (AS), 
Inflammatory Bowel Disease (IBD), and Rheumatoid Arthritis (RA). 
8. 
Pregnancy or breast feeding. 
9. 
Active second invasive malignancy, other than basal cell carcinoma of the skin. 

 
 
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10. 
Life expectancy of less than 6 months. 
11. 
Patients with contraindications to known allergies to CYP and/or Imiquimod. 
12. 
Patients who have received organ transplants. 
13. 
Patients with psychological or geographic conditions that prevent adequate follow-
up or compliance with the study protocol. 
3.3 
Withdrawal Criteria 
3.3.1 Reasons for Withdrawal of Patients from Study 
1. 
Patients with clinically significant biochemical, histological and/or radiographic 
evidence of increasing disease burden since entry into the study may be removed 
from the study. 
2. 
Patients may be withdrawn from the study in the event of dose limiting toxicities. 
3. 
Patients may be withdrawn from study in the event of protocol non-compliance. 
4. 
Patients may voluntarily withdraw from study, if they decide to do so, for any 
reason. 
3.3.2 Follow-up of Withdrawn Patients 
1. 
A subject withdrawn by virtue of progressive disease will continue to be followed 
as clinically indicated, as determined by the patient’s physician and will continue 
to receive standard of care follow-up, as medically indicated and at the discretion 
of the patient’s physician. 
2. 
A subject withdrawn by virtue of limiting treatment-related toxicity will be 
followed as clinically indicated, as determined by the patient’s physician per 
standard of care, and/or until resolution of the adverse event(s). 
3. 
All subjects will be requested to adhere to the protocol schedule for clinic visits as 
far as is reasonable and as clinically indicated. 
4. 
Blood draws and protocol related data will be requested and collected according to 
the protocol schedule as is reasonable and as clinically indicated. 
5. 
As far as is reasonable, data will continue to be collected at the indicated protocol 
time-points. 
3.4 
Patient Replacement 
3.4.1 Reasons for Replacement 
1. 
In the event of screening failures post-enrollment (i.e., patients without confirmed 

 
 
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progressive and/or relapsed SM diagnosis or failure to meet other screening or 
inclusion criteria), patients will be replaced. 
2. 
Inability of enrolled subjects to tolerate phlebotomy or leukapheresis. 
3. 
Voluntary withdrawal of subjects prior to initiation of treatment. 
4. 
Failure to complete three (3) DC vaccinations. 
3.5 
Study Schedule  
3.5.1 Summary of Pre-treatment Evaluations 
1. 
Obtain informed consent to enroll patients with refractory SM s/p conventional 
salvage therapy. 
2. 
Completion of screening procedures per study calendar (including determination of 
TAPA expression in neoplastic cells and/or blood) and pre-treatment evaluation for 
clinical trial enrollment. 
3. 
Completion of systemic therapy and confirmation of refractory, progressive, and/or 
relapsed SM. 
4. 
CBC, differential leukocyte counts, and baseline biochemical and/or radiographic 
evaluation of disease status no more than per study calendar.  
5. 
Pregnancy evaluation. 
6. 
Completed baseline delayed-type hypersensitivity response (DTH) skin tests with 
specific TAPA(s) seven (7) days +/- 3 days prior to 1st DC vaccination. 
7. 
Negative infectious disease history, for safe handling of blood/leukapheresis 
products (including a negative history of HIV, and a negative history of active 
hepatitis A, B, or C). 
8. 
Phlebotomy/leukapheresis within 2 weeks +/- 7 days prior to beginning DC 
vaccination schedule. 
9. 
Manufacturing of DC vaccine bank. 
10. 
Baseline Immune Assays and tissue TAPA levels. 
11. 
Initiation of treatment a 5-day course of CYP, which may be taken at home, 
beginning 5-7 days prior to each DC vaccination.  
3.5.2 Summary of Treatment Visits and Procedures 
1. 
Please refer to Appendix 1, Study Calendar   

 
 
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3.6 
Safety Endpoints  
The main endpoints for this Phase I/II trial are safety and immune efficacy.  Up to six (6) 
patients will be enrolled in the Phase I/toxicity stage of the study.  Early stopping rules will 
be in place to protect patients from excessive toxicity.  The trial will be halted if Dose 
Limiting Toxicity (DLT, defined below) occurs in two (2) or more of six (6) patients 
receiving DC vaccination.   
If DLTs are observed in no more than 1/6 patients during the Phase I/toxicity stage, the 
treatment will advance to the Phase II/immune efficacy stage.  Immune efficacy will be 
evaluated in all patients (see below for stopping rule regarding lack of immune 
efficacy). 
Toxicity will be graded according to NCI-CTCAE, version 4.0. 
3.6.1 Rules Based on Dose Limiting Toxicity  
   
 
 
 
3.6.2 Definition of Adverse Event and Adverse Reaction 
1. 
An adverse event is defined as any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related.  More 
specifically, an adverse event can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a drug, without any judgment about causality.  An adverse event can arise 
from any use of the drug (e.g., off-label use, use in combination with another drug) 
and from any route of administration, formulation, or dose, including an overdose. 
2. 
An adverse reaction is defined as any adverse event caused by the use of a drug.  
Adverse reactions are a subset of all suspected adverse reactions for which there is 
reason to conclude that the drug caused the event. 
3.6.3 Causality 
1. 
Suspected  
A suspected adverse reaction is defined as any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of 
IND safety reporting, “reasonable possibility” indicates that there is evidence to 
suggest a causal relationship between the drug and the adverse event.  A suspected 
adverse reaction implies a lesser degree of certainty about causality than an 
adverse reaction. 
Patients with DLTs Action 
0-1/6 
Proceed to the immune efficacy stage of the study 
≥ 2/6 
Stop study 

 
 
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2. 
Unexpected  
 
An adverse event or suspected adverse reaction is considered unexpected if it is not 
listed in the investigator brochure or package insert(s), 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 or elsewhere in the current application. Adverse events 
that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a 
cancer trial would be anticipated as an outcome of the underlying disease, but such 
deaths would generally not be listed as a suspected adverse reaction in the 
investigator brochure.  Some adverse events are listed in the Investigator Brochure 
as occurring with the same class of drugs, or as anticipated from the 
pharmacological properties of the drug, even though they have not been observed 
with the drug under investigation.  Such events would be considered unexpected 
until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in 
the ACE inhibitor class and angioedema would be described in the investigator 
brochure as a class effect, the first case of angioedema observed with the drug under 
investigation should be considered unexpected for reporting purposes. 
3. 
Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view 
of either the investigator or sponsor, it results in any of the following outcomes:  
a. 
Death 
b. 
Life-threatening adverse event 
c. 
Inpatient hospitalization or prolongation of existing hospitalization 
d. 
A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life function 
e. 
Congenital anomaly/birth defect 
f. 
Important medical events that may not result in death, are life-threatening, 
or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room 

 
 
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or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
4. 
Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in 
the view of either the investigator or sponsor, its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused 
death.  
3.6.4 Recording of Adverse Events (AE) 
1. 
All grade 3 and above AE will be recorded whether or not the event is believed to 
be associated with use of the study drug.  Data about these events and their severity 
will be recorded using the NCI CTCAE version 4.0.   
2. 
The Investigator will assign attribution of the possible association of the event with 
use of the investigational drug, and this information will be recorded using the 
classification system listed below:  
a. 
Unrelated to investigational drug/intervention:  The AE is clearly NOT 
related to the intervention  
b. 
Unlikely related to investigational drug/intervention:  The AE is doubtfully 
related to the intervention  
c. 
Related to investigational drug/intervention: 
 
• 
Possible: The AE may be related to the intervention  
• 
Probable: The AE is likely related to the intervention  
• 
Definite: The AE is clearly related to the intervention  
3. 
Signs or symptoms reported as AE will be graded and recorded by the Investigator 
according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v. 4.0.  When specific AE are not listed in the NCI-
CTCAE v. 4.0, they will be graded by the Investigator as none, mild, moderate, or 
severe according to the following grades and definitions: 
a. 
Grade 0: 
No AE (or within normal limits) 
b. 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or       
diagnostic observations only; intervention not indicated 
c. 
Grade 2: 
Moderate; minimal, local, or noninvasive intervention (e.g., 

 
 
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packing, cautery) indicated; limiting age-appropriate instrumental activities 
of daily living (ADL) 
d. 
Grade 3: 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL 
e. 
Grade 4: 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
f. 
Grade 5: 
Death related to AE 
3.6.5 Follow-up of Adverse Events 
1. 
All adverse events will be followed with appropriate medical management until 
resolved.   
2. 
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.   
3. 
For selected adverse events for which administration of the investigational drug 
was stopped, a re-challenge of the subject with the investigational drug may be 
conducted if considered both safe and ethical by the Investigator. 
3.6.6 Adverse Event Monitoring  
1. 
All AE, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be recorded, as noted above. 
2. 
The Principal Investigator (PI) will assess all AE and determine reportability 
requirements to the Food and Drug Administration (FDA), if it meets the FDA 
reporting criteria. 
3. 
All AE recorded will be reviewed by the study PI on a weekly basis and the 
Institutional Protocol Review Committee (IPRC) and/or the Institutional Review 
Board (IRB) on a monthly basis, or as deemed necessary by the study PI.  The 
PI/IPRC will review and discuss at each meeting the selected toxicity, the toxicity 
grade, and the attribution of the relationship of the AE to study drug/treatment. 
3.6.7 Definition of Dose-Limiting Toxicity (DLT) 
1. 
Grade III or higher allergic reaction. Grade III is defined as symptomatic 
bronchospasm requiring medication, edema or angioedema, and Grade IV is 
defined as anaphylaxis. 
2. 
Grade II or higher autoimmune reaction. Grade II is defined as an autoimmune 
reaction involving a non-essential organ or function requiring treatment. 

 
 
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3. 
Grade III or higher hematologic or non-hematologic toxicity including fever (> 40o 
C for > 24 hours). 
4. 
Grade III injection site reaction (severe or prolonged ulceration or necrosis). 
5. 
Toxicity will be graded according to NCI-CTCAE, version 4.0. 
3.7 
Immune Efficacy Endpoint 
3.7.1 Immune Efficacy (IE) Rules  
The main secondary endpoint of this Phase I/II clinical study is immune efficacy (IE), 
defined as “detection of a TAPA-specific immune response in SM patients receiving DC 
vaccination”.  Immune responses will be evaluated, as described, in all patients enrolled 
on the study.  Up to six (6) patients will receive the planned six three (3) DC vaccinations 
before with an interim analysis of IE performed on Day 22 and Day 45 of the sixth patient 
(69).  With regard to IE, the accrual goal will be up to seventeen (17) patients.  Stopping 
criteria, with regard to IE, will be based on defined immune responses and will follow a 
Simon 2-stage design with a null hypothesis of 5% IE (p0 = 0.05) and alternative hypothesis 
of 35% IE (p1 = 0.35) with desired significance level (α) and desired power (1-β) of 0.05 
and 0.9, respectively.  Interim analysis of immune response will be conducted after accrual 
of six (6) subjects completing the planned three (3) DC vaccine doses. If no immune 
responses are observed at interim analysis (0/6 patients), early stopping will be 
considered based on lack of efficacy of the intervention. With this rule, the probability 
of early termination (if the alternative hypothesis is true) is seven and one-half percent 
(7.5%).  If three (3) or more patients, out of a total of seventeen (17) develop TAPA-
specific immune responses, then the null hypothesis of 5% IE can be rejected, and results 
will be deemed favorable to move to a formal phase II study. Analysis to determine IE will 
be performed in all patients after receiving six three (3) DC vaccine doses.  
Patients who are unable to complete the planned six three (3) DC vaccine doses will be 
withdrawn from the study.      
1. 
Immune Efficacy Endpoint will be determined as follows: 
a. 
Positive T-cell cytokine IFN-ɣ, and/or TNF-α, and/or IL-17 ELISpot assay 
for ex vivo T cell cytokine expression following stimulation with relevant 
TAPA. For each patient sample the IFN-γ ELISpot assay (and/or TNF-α or 
IL-17) will be performed in triplicate using a minimum of three wells per 
replicate, as described by the manufacturer. 
b. 
Positive DTH skin tests with relevant TAPA (DTH skin tests will be 
performed on subject’s forearm or within 5 cm from the site of prior DC 
vaccination, if possible). 

 
 
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3.8 
Reasons for Discontinuation of Study 
1. 
High frequency of limiting toxicities.  
2. 
Lack of immune response. 
3. 
Non-availability of reagents required for DC manufacture (including non-
availability of acceptable alternative reagents). 
4. 
Non-availability of Imiquimod and/or oral CYP, in the absence of an available 
alternative. 
3.9 
Potential Risks and Benefits 
3.9.1 Known Toxicities Associated with DC Vaccination  
1. 
DC vaccination strategies have been studied clinically in many different diseases. 
This particular vaccine has been tested in very few patients. Both monocyte-derived 
DCs (as being proposed for this study) and CD34+-derived DCs have been used in 
the presence of serum-free or fetal calf serum-containing mediums. Because these 
cells have been generated from autologous cells, their administration either 
intravenously (IV), subcutaneously (SC) or intradermally (ID) has not been 
associated with any significant adverse effects, with the exception of low grade 
fever and local reactions, such as erythema, at the sites of injection. 
2. 
In a recently conducted phase I clinical trial of DC vaccination of patients with 
early-stage cervical cancer (BB-IND 11307), no adverse side effects were observed 
or reported by subjects following immunization beyond the immediate discomfort 
associated with injection (10). However, local reactions (mild erythema, 
swelling/induration, pruritus) were noticed at the subcutaneous vaccination sites 
that increased with the number of vaccinations in most of the patients. Also, a slight 
enlargement in the draining lymph node in the groin after DC injections was 
observed in some of the patients.  The patients were monitored during treatment 
with complete blood counts and serum chemistries that included liver and renal 
function tests and electrolytes. No alterations in liver and renal function were 
detected.  The safety of DC vaccination was also recently demonstrated in a study 
combining autologous DC vaccine against the melanoma antigen MART-1 and the 
cytotoxic T lymphocyte associated antigen 4 (CTL-4) antagonist tremelimumab 
(70).  The only toxicity reported in this study was related to grade I-II pruritic skin 
eruptions previously associated with CTLA4 antagonists.  No toxicity attributed to 
DC vaccination alone was reported.  
3. 
One of the major concerns regarding DC vaccination with self-tumor antigens is 
the possible induction of autoimmunity.  Vitiligo has been seen in some melanoma 

 
 
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patients, but no cases of severe autoimmune reactions have been reported.  Some 
TAPAs used in this study have not been explored as targets for immunotherapy in 
large numbers of patients.  Therefore, the clinical data supporting their safety in 
humans is limited (30). Nevertheless, the available data indicating these TAPAs are 
selectively expressed in tumor cells and normal testis (but not in any normal tissues) 
suggest the immune responses generated by TAPA-pulsed DC therapy will only 
affect tumor cells. Further evidence supporting the safety of TAPA immuno-
targeting is the lack of toxicity associated with spontaneous development of anti-
TAPA antibodies following vasectomy (25). Despite these observations, the 
possible risks of stimulating Th17 responses through DC vaccination in SM 
patients, are not known.  Interestingly, a number of studies have documented 
contradictory results on the effects of stimulating Th17 T cell responses, with some 
showing potent anti-tumor activity for Th17 T cells, while others reporting pro-
angiogenic and tumor-promoting properties ascribed to Th17 immune responses 
(71). Moreover, since Th17 responses are pro-inflammatory, they may be 
associated with as yet unknown side effects. Despite these potential problems, the 
available 
evidence 
suggests 
the 
risk 
of 
developing 
autoimmune 
complications/disease should be minimal. Also, since the majority of these TAPAs 
are expressed in spermatids, there is also a remote possibility that normal testicular 
function may be affected. All subjects will be monitored closely for treatment-
related adverse events and dose-limiting toxicities.  
4.0 METHODS AND ASSESSMENTS 
4.1 
Contraception and Pregnancy Testing 
Either a female or male of reproductive capacity wishing to participate in this study must 
be using, or agree to use, one or more types of birth control during the entire study and for 
3 months after completing the study.  These may include condoms, diaphragms, birth 
control pills, spermicidal gels or foams, anti-gonadotropin injections, intrauterine devices 
(IUD), surgical sterilization, or subcutaneous implants.  Another choice is for a subject’s 
sexual partner to use one of these birth control methods. Women of reproductive capacity 
will be requested to undergo a urine pregnancy test before completion of the post-screening 
informed consent process. 
 4.2 Screening, Study Visits and Procedures 
4.2.1 Screening Visits and Procedures  
1. 
Subjects must be adult patients with confirmed progressive and/or refractory SM 
and no available, potentially curative therapeutic option. Informed consent will be 
sought for completion of screening procedures. 
2. 
Screening evaluation will include the following: 

 
 
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a. 
History and physical examination. 
b. 
Karnofsky performance status. 
c. 
Evaluation of concomitant medications. 
d. 
CBC and differential leukocyte count. 
e. 
Tests for hepatic function and renal function. 
f. 
Pregnancy evaluation and birth control agreement.  
g. 
Negative 
infectious 
disease 
history, 
for 
safe 
handling 
of 
blood/leukapheresis products (including a negative history of HIV, and a 
negative history of active hepatitis A, B, or C). 
h. 
Diagnostic studies, including biopsies (if indicated), appropriate imaging 
studies, serum and/or urine tumor marker measurements (if indicated), will 
be obtained within three (3) weeks ±14 days prior to vaccination. 
i. 
Confirmation of expression of one (1) or more TAPA, by either RT-PCR, 
immunohistochemistry, Western blotting, or ELISA, in neoplastic cells 
prior to enrollment. For HER-2/Neu expression a positive FISH will be 
considered adequate. 
4.2.2 Study Visits and Procedures 
1. 
Peripheral blood mononuclear cells will be harvested by phlebotomy and/or 
leukapheresis, via peripheral or central venous access.  
 
Patients must be willing to provide at least 250 mL, and up to 500 mL, of whole 
blood obtained by phlebotomy and/or consent to leukapheresis for DC generation.  
 
If leukapheresis is required, this procedure will require a median duration of 2-3 
hours on a leukapheresis machine and a median volume of processed whole blood 
of 150 ml/kg body weight.  This can be done with a large bore peripheral IV but in 
select patients it may require a temporary central line during the procedure. The 
end result is a rich collection of nucleated white blood cells from which to extract 
DC precursors. The total volume of removed blood product is a small bag 
containing approximately 100 cc of plasma which contains the desired cells. 
Central venous access will be placed and used for phlebotomy/leukapheresis only 
if blood cannot be obtained by peripheral access. Placement of central venous 
access will be done at the hospital as an outpatient and with a separate surgical 
consent. 

 
 
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Phlebotomy/leukapheresis will be conducted within two (2) weeks +/- 7 days of the 
first DC vaccination.   
2. 
The patient will receive a 5-day course of CYP (1.6 mg/Kg/day, with a maximum 
of 100 mg/day), which may be taken at home, beginning 5-7 days prior to each DC 
vaccination.  
3. 
TAPA-pulsed DC will be administered at a vaccine dose of up to 1 x 107 DC, in 
injection-grade saline solution to bring total volume to 1 mL, if necessary. The 
vaccine total volume will be up to 1.0 mL and will be administered in 4 separate 
intradermal (ID) injections (0.25ml per injection) in the upper anterior thigh 
(inguinal node region) or the upper outer arm (axillary node region) in order to 
increase proximity to local lymph node draining basins and optimize propagation 
of TAPA-pulsed DCs to secondary lymphoid organs (72). If clinically feasible, 
DC vaccination will be alternated between the right and left sides of either the 
upper anterior thigh, or the upper outer arm. If there is the history of a prior 
inguinal lymphadenectomy, lower extremity lymphedema, prior inguinal hernia 
repair, or, the history of an axillary lymph node dissection, or upper extremity 
lymphedema, then the non-affected site/anatomic region would be preferred. The 
three (3) DC vaccines will be administered at 7-day intervals to maximize patient 
convenience and protocol adherence. Patients will be observed for up to one (1) to 
three (3) hours following each vaccine dose administration. 
 
 
 
4. 
Vaccination Schedule: 
Day 1 
Day 8 
Day 15 
Vaccine 1 
Vaccine 2 
Vaccine 3 
 
Imiquimod cream will be administered at a dose of ~10 mg after each intradermal 
injection. Immediately after the injections, the area will be cleaned by gently 
tapping with an alcohol swab (such as BD Alcohol Swabs). When the area is dry, 
Imiquimod (Aldara cream) will be applied over the injection sites, at the dose of 
about 4 mm of cream, corresponding to 10 mg Imiquimod. The area will be covered 
with a Band-Aid type patch and the patient will be instructed not to wash it or wipe 
it until the following day, when the patient will remove the medication by washing 
the area with mild soap and water. If itchiness is present, the patient will be 
instructed to apply topical anti-histamine cream as appropriate. Steroid-based 
medication at the site of the injection are to be avoided. 
 

 
 
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5. 
Blood for immune assays and TAPA levels (up to 100 mL) will be drawn 1 to 7 
days +/- 3 days before the 1st DC vaccination, and on days twenty-two (22) and 
day forty-five (45) +/- 3 days after the third vaccination.  
6. 
DTH skin tests to assess cellular immune responses against relevant TAPAs will 
be conducted at the same time of blood immune assays (see above). DTH response 
will be determined and the response measured, between 2 and 3 days following the 
skin test, the results of which can be read by the study coordinator or by an 
appropriate study coordinator designated health care professional.   
7. 
Evaluation of tumor responses: 
Immune responses shall be evaluated 7 days (Day 22) and 30 days (Day 45) 
following the last (3rd) DC vaccination, with imaging as clinically indicated (See 
Appendix 3).  Patients may undergo evaluation of disease status anytime, at the 
discretion of PI, if disease progression is suspected.   
8. 
Patient Enrollment 
Once the Phase I stage of the study is completed (subject 6 receives the 3rd 
vaccination dose and is evaluated for toxicity) the Phase II stage of the study will 
begin with enrollment of subject # 7. 
9. 
All clinical laboratory tests will be performed in a CLIA and/or ISO-certified 
facility.  Non-clinical tests (i.e., IHC/PCR/ELISA tests for evaluation of TAPA 
expression, ELISPOT for evaluation of immune response, etc.) will be performed 
in CLIA and/or ISO-certified facilities whenever possible.   
4.2.3 Final Study Visit 
1. 
The final study visit will take place 30 days (Day 45) +/- 3 days after the last DC 
vaccination. Procedures will include a blood draw and DTH skin tests for 
responsiveness to TAPAs. 
2. 
Laboratory tests at the final study visit will include serum tumor markers (if 
indicated), hepatic and renal profile, CBC, and differential leukocyte counts. 
3. 
Appropriate imaging studies and other relevant tests for determining disease status 
(i.e., cytogenetics, etc.) will be also obtained as clinically indicated. 
4.2.4 Post-Study Follow-up  
1. 
Blood for immune assays (up to 100 ml) will be drawn 7 days prior to the first 
vaccination and again at day 22 and day 45. 

 
 
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4.2.5  Discontinuation Visit  
1. 
Will be identical to final study laboratories/procedures.  Procedures will include a 
blood draw and skin tests for responsiveness to TAPAs. 
2. 
Laboratory tests at the final study visit will include hepatic and renal profile, CBC 
and differential leukocyte counts. 
3. 
Imaging studies and other relevant test for determining disease status will be 
obtained, if necessary. 
5.0 STUDY MATERIALS AND PROCEDURES 
5.1 
Products 
5.1.1 TAPA-Pulsed Dendritic Cells (DCs) 
The procedure for generating TAPA-pulsed DCs suitable for clinical use will be carried 
out at Kiromic’s Cell Processing laboratory specifically designed for the generation of 
GMP clinical grade cellular materials. DCs will be derived from monocyte precursors 
present in peripheral blood mononuclear cells (PBMC) cultures following phlebotomy 
and/or leukapheresis.  PBMC will be separated by Ficoll gradients and/or CliniMACs 
separation system and cultured in CellGro medium (CellGenix, USA), IL-4 and GM-CSF 
(CellGenix, USA) for up to seven (7) days.  DCs will be grown in culture flasks and/or G-
Rex growth system and vaccine will be prepared by exposing DCs to a maturation cytokine 
cocktail (IL-1β and TNFα (CellGenix, USA), poly (I: C) (InvivoGen, USA) and INFα for 
16-72 hrs.  DCs will then be “pulsed” with relevant, recombinant TAPAs for 2-4 hours. 
Successful generation of mature DCs will be confirmed in each case by 
immunophenotyping for classical DC markers, including CD1a, CD58, CD80, CD83, 
CD86 and HLA-DR.  Recombinant, clinical grade TAPAs will be obtained from CS Bio 
Company, Inc. a company specialized in manufacturing cGMP peptides located at 20 
KELLY CT. Menlo Park, CA 94025. Following the maturation period DCs will be 
aliquoted into six or more equal volumes for cryopreservation until further use.  
Alternatively, one DC vaccine dose will be manufactured, with additional doses prepared 
subsequently from cryopreserved PBMNCs.  DCs may also be generated following the 
same but inverted procedure (TAPA pulsing prior to exposure to maturation cytokine 
cocktail, See SOP).   
All reagents and plastics to be used for this purpose will be stored at Kiromic’s GMP 
laboratory and used solely for the DC generation and maturation process. All procedures 
will be carried out in sterile conditions and the final products will be evaluated by an 
independent CLIA-certified laboratory for sterility, including presence of endotoxin, 
mycoplasma contamination, fungal, aerobic and anaerobic bacterial cultures and Gram 
staining, prior to human administration. Results of these tests will be obtained prior to 
release of the final product for human administration.  Mature DCs (or PBMCs for later 
generation of fresh mature DCs) will be cryopreserved and stored in a dedicated liquid 

 
 
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nitrogen container at Kiromic, until being used. 
5.2 
Storage and Drug Accountability 
5.2.1 TAPA-Pulsed Dendritic Cells (DCs) 
1. 
A minimum of three (3) and a maximum of six (6) vials of TAPA-pulsed DCs 
(containing up to 1 X 107 DCs each) will be cryopreserved as a master vaccine bank 
for each patient.  TAPA-pulsed DC vaccine will be frozen in 90% heat-inactivated 
normal human AB serum and 10% dimethyl sulfoxide.  Alternatively, an aliquot of 
the original pool of PBMCs will be cryopreserved, as described above, for 
subsequent thawing and generation of fresh DCs prior to each vaccination schedule 
(see SOP).  This process may improve the viability of DCs. A dedicated liquid 
nitrogen storage container will be used exclusively for patient PBMCs and DC 
vaccine preparations for this study.   
2. 
All specimens and vaccines will be transported to/from the participating institution 
in compliance with standard biohazard protocol. 
6.0 TREATMENT 
6.1 
Selection of TAPA-Pulsed DC Dose Level 
6.1.1 Rationale 
A phase I dose escalation clinical trial of DC vaccination in patients with cervical cancer 
indicated optimal stimulation of tumor antigen-specific cytotoxic T cell responses with a 
dose of up to 1.0 x 107 DCs and delivered SC and ID at 21 day intervals (10).  Thus, in this 
study we will explore one (1) dose of TAPA-pulsed DC vaccination (up to 1 X 107 DCs) 
and determine the toxicity, immune efficacy (IE) and clinical response in patients with 
progressive and /or refractory SM without available, potentially curative therapeutic 
options.   
Preliminary studies indicate that leukapheresis (10-liter volume) followed by CliniMACS 
isolation of CD14+ cells and high-density DC culture in G-Rex flasks provides an optimal 
yield of 2.5 x108 mature DCs from 109 CD14+ cells. This would be sufficient for 
cryopreservation of 12 vials at 1 x107 DC/vial.  Phlebotomy of 250 mL of whole blood 
yields approximately 1.2 X 108 monocytes and 3 X 107 mature DCs (see Section 7.2).  The 
CliniMACS separation system and the G-Rex DC growth system may be used as an 
alternative to Ficoll-gradient monocyte separation and standard DC growth protocol using 
flasks.  
 
6.1.2 TAPA-Pulsed DC Vaccination 
This is a phase I/II safety and efficacy study.  Only one dose level of TAPA-pulsed DC 
will be used. 

 
 
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Dose 
Level 
Minimal 
Number of 
Patients 
DCs per 
Vaccination 
 
1 
6 
1 x 107 
The first six (6) patients will receive up to 1 x 107 DCs divided into 4 intradermal (ID) 
injections, every seven (7) days, for up to a maximum of six three (3) treatments. The (ID) 
DC vaccinations will be administered in an approximate volume of 0.25 ml per injection 
site (total vaccination dose-volume 1.0 ml).  Thirty minutes prior to receiving the DC 
vaccination, all patients will receive premedication with diphenhydramine (12.5-50 mg) 
and acetaminophen (325-1000 mg) orally.  Topical lidocaine based anesthetic applications 
may also be administered prior to the vaccination at the discretion of the study coordinator.   
During the Phase I stage of this study up to six (6) consecutive subjects will be enrolled.   
If one (1) or less than six (6) patients develops DLT, the Phase II/immune efficacy stage 
will proceed.  If two or more (≥ 2) of the first six (6) patients develop DLTs, the study will 
be terminated.  A minimum of six (6) patients will be treated for evaluation of 
safety/toxicity (Phase I level). If toxicity criteria for continuation is fulfilled during the 
phase I stage, patient enrollment in the Phase II/immune efficacy stage may proceed. Up 
to seventeen (17) patients will be treated in the study for evaluation of immune efficacy 
and possible clinical response (Phase II stage), with IE determined following completion 
of three (3) DC vaccine doses (day 22 and day 45).  
6.1.3. Imiquimod Treatment 
Following each DC vaccination, the patient will receive a single dose of Imiquimod cream. 
6.2 
Study Drug Administration 
6.2.1 Cyclophosphamide (CYP) 
 
The patient will receive a 5-day course of CYP (1.6 mg/kg/day with maximum dose of 100 
mg/day), which may be taken at home, beginning 5-7 days prior to each DC vaccination.   
6.2.2  TAPA-Pulsed Dendritic Cells (DC) 
 
TAPA-pulsed DC will be administered at a vaccine dose of up to 1 x 107 DC, in 
injection-grade saline solution to bring total volume to 1 mL, if necessary. The vaccine 
volume will be up to 1.0 mL and will be administered in 4 separate intradermal (ID) 
injections at the 12 o’clock, 3 o’clock, 6 o’clock and 9 o’clock positions in the upper 
outer arm or the upper anterior thigh region) in order to increase proximity to local lymph 
node draining basins and optimize propagation of TAPA-pulsed DCs to secondary 
lymphoid organs. Thus approximately 0.25 mL will be injected at each injection site 
(total volume 1.0 mL). Axillary lymph node region area is the preferred vaccination site 
for this study.  DC vaccination will be alternated between the upper outer arm, and upper 
anterior thigh of both limbs. Three (3) DC vaccines will be administered at 7-day 
intervals.  Patients may be observed for up to one (1) to three (3) hours following each 
vaccine dose administration. 

 
 
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6.3 
Study Drug Quality and Safety Measures 
6.3.1 TAPA-Pulsed Dendritic Cells (DCs) 
1. 
TAPA-pulsed DCs will be administered ID at 7-day intervals.  plus or minus 2 days. 
2. 
Safety tests before release of TAPA-pulsed DCs: 
a. 
Bacterial and fungal sterility test. 
b. 
Mycoplasma test. 
c. 
Endotoxin test: Endotoxin must be less than 1 IU/ml by the LAL method. 
3. 
Plan of action in the event of DC vaccine test failures: 
a. 
If a sterility and/or endotoxin test is positive, the vaccine dose will be 
discarded.  A second dose of DC vaccine will be thawed and tested.  If test 
results on the second dose are negative, the patient will receive treatment.  
If test results on the second dose are positive, the entire batch of DC vaccine 
will be discarded, and the patient will be withdrawn from study. 
b. 
In the unlikely event that a dose gives a positive result by bacterial growth 
test (agar sterility test) after administration to the patient, the patient’s 
physician will be notified immediately, with the recommendation that the 
patient be treated with antibiotics, even if the patient shows no clinical signs 
of infection.  A second DC vaccine dose will be thawed and subjected to 
the bacterial growth test.  If the second dose tests positive, the DC vaccine 
batch will be discarded, and treatment discontinued.  If the second dose tests 
negative, patient treatment will proceed. 
c. 
If an entire DC vaccine batch is discarded, treatment may proceed if it is 
possible to prepare a new vaccine batch (usually contingent on a second 
leukapheresis/phlebotomy procedure). 
4. 
All clinical laboratory tests will be performed in a CLIA certified facility. 
6.4 
Specific Restrictions and Requirements 
6.4.1 Concomitant Therapy  
1. 
Immunosuppressive or anti-inflammatory drugs (including hydrocortisone) that 
inhibit cellular immune responses should not be taken, unless otherwise indicated 
for the management of study-related toxicities, adverse events, symptomatic 

 
 
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disease progression, or pre-existing conditions (i.e., chronic adrenal cortical 
insufficiency). All medications (prescription and over the counter), vitamin and 
mineral supplements, and/or herbs taken by the study subjects will be documented. 
Topical steroids are permissible. 
 
6.4.2 Compliance with Therapy 
1. 
All treatments and study procedures will be administered in the clinic except for 
the cyclophosphamide that can be taken at home as per the protocol schedule.  
7.0 SAMPLE SIZE AND STATISTICAL METHODS 
7.1 
Determination of Sample Size 
7.1.1 Sample Size for Safety Evaluation  
An initial cohort of up to six (6) subjects will receive low-dose CYP, TAPA-pulsed DC 
vaccination and topical Imiquimod for determination of safety/toxicity (phase I stage).    
7.1.2 Sample Size for Evaluation of Immune Efficacy 
Up to seventeen (17) patients may be enrolled for evaluation of immune efficacy (Phase II 
stage).  Enrollment will begin if toxicity criteria are fulfilled and interim evaluation of IE 
is completed during the phase I stage (first 6 patients). Stopping criteria for the study, based 
on IE, will follow the Immune Efficacy Rules described in 3.7.1.   
7.2 
Statistical Methods 
7.2.1  Safety and Toxicity  
A single dose of CYP, TAPA-pulsed DC vaccine and topical Imiquimod will be evaluated 
in this study.  Six (6) consecutive patients will be treated as proposed for toxicity evaluation 
(Phase I stage).  If no limiting toxicity is encountered, additional patients will be enrolled 
to determine immune efficacy (Phase II stage).   
 
7.2.2 Immune Efficacy (IE) 
For the IE part of the study, a Simon 2-stage design with a null hypothesis of 5% IE (p0 = 
0.05) and alternative hypothesis of 35% IE (p1 = 0.35), with desired significance level (α) 
and desired power (1-β) of 0.05 and 0.9, respectively, will be utilized.  An interim analysis 
of immune response will be conducted after accrual and treatment of the first six (6) 
patients, following completion of the planned six three (3) DC vaccine doses, with immune 
response evaluation on day 22 and day 45. Patients who are unable to complete the planned 
six three (3) DC vaccine doses will be withdrawn from the study.  
 
If no immune responses are observed at interim analysis, termination of the study will be 
considered based on lack of efficacy of the intervention.  The probability of early 
termination, if no immune responses are observed in the first six (6) patients and the 
alternative hypothesis is true, is 7.5%. If 3 or more responses out of a total of 17 patients 

 
 
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are observed, the null hypothesis can be rejected and DC vaccination may move to a formal 
Phase II/III developmental stage.   
8.0 ETHICAL CONSIDERATIONS 
8.1 
Protection of Patients from Unnecessary Harm  
Safety of subjects involved in human experimentation is protected by both the participating 
clinical investigators and independently by the Institutional Protocol Review Committee 
(IPRC) and/or the Institutional Review Board (IRB).  The IRB reviews all proposed studies 
involving human experimentation and ensures that the subject’s rights and welfare are 
protected and that the potential benefits and/or the importance of the knowledge to be 
gained outweigh the risks to the individual. The IRB also reviews the informed consent 
document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its associated 
risks and benefits.  
8.2 
Privacy and Confidentiality   
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, 
they will be asked to sign the HIPAA form and informed consent documents. The original 
signed document will become part of the patient’s medical records, and each patient will 
receive a copy of the signed document. The use and disclosure of protected health 
information will be limited to the individuals described in the informed consent document. 
In order to protect patient’s privacy, all study data will be identified only by initials and a 
specifically assigned study number. However, in compliance with Good Clinical Practices, 
the PI will allow the independent study monitor(s) to review that portion of the patient’s 
medical record that is directly related to the study.  This shall include all relevant study 
documentation, including patient medical histories to verify eligibility, laboratory test 
results, x-ray reports, and admission/discharge summaries while the patient is on-study, 
and autopsy reports for deaths occurring during the study (if available).  
8.3 
Informed Consent 
In obtaining and documenting informed consent, the investigators will comply with the 
IRB guidelines and the ethical principles originating in the Declaration of Helsinki. 
8.4 
IRB Approval 
This protocol and the associated informed consent documents must be submitted to the 
IRB for review and approval.  

 
 
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9.0 SAFETY CONSIDERATIONS 
9.1 
TAPA-Pulsed DC Vaccination 
DC-based treatments have been applied and studied clinically in many different diseases.  
Both monocyte-derived DCs (as being proposed for this study) and CD34+-derived DCs 
have been used in the presence of serum-free or autologous serum-containing mediums. 
Because these cells have been generated from autologous cells, their administration 
intravenously (IV), subcutaneously (SC) or intradermally (ID) has not been associated with 
any significant adverse reactions, with the exception of low grade fever and local reactions, 
such as erythema, at the sites of injection (See discussion above). 
9.2 
Adverse Immune Responses Against TAPA-Pulsed DC Vaccinations 
The specific panel of TAPAs used in this study is novel and has not been explored 
extensively as a target for immunotherapy in humans. Therefore, there is no significant 
clinical data to support its safety in patients. Nevertheless, the available data showing these 
TAPAs are selectively expressed in tumor cells and normal testis (but not in normal 
tissues), it is expected the immune responses generated by TAPA-pulsed DC therapy will 
only affect tumor cells (and possibly normal testis). Further evidence supporting the safety 
of TAPA immunotargeting is the lack of toxicity associated with spontaneous development 
of anti-TAPA antibodies following vasectomy (25).    
9.3 
Regulatory Aspects 
This study will be conducted as part of an Investigational New Drug (IND) Application 
approved by the FDA (IND #12612). The study will not commence until full approval is 
obtained from either the central and/or local IRB. 
 
10.0 FINANCIAL CONSIDERATIONS 
The expenses and costs incurred by this study for the generation and processing of TAPA-
pulsed DC vaccines, oral CYP dose, topical Imiqumod, and leukapheresis/phlebotomy, 
will be provided by financial support entirely or partially from Kiromic, and/or external 
funding sources.  It is expected that standard of care treatments and studies during and after 
the course of the study plus the follow-up monitoring (as part of the standard of care for 
patients with SM) will be paid either by the patient or their insurance companies. This 
arrangement will be clarified in the Patient Consent Form. 
11.0 POTENTIAL CONFLICT OF INTEREST 
It is possible that in the future Kiromic, may apply for a patent covering the potential use 
of some TAPAs in cancer therapeutics and diagnostics. The investigators will declare this 
potential conflict of interest in the Patient Consent Form so that all patients recruited to this 
study will be aware that some or all data obtained may be used to support future application 
that may result in commercial value of the DC vaccination strategy.  A panel of independent 

 
 
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physicians/investigators will serve as an external Independent Clinical and Scientific 
Review Board monitor team (ICSRB) that will review the clinical and immunologic data 
generated in the study in order to guarantee the un-biased evaluation of study results.      
12.0 QUALITY CONTROL AND QUALITY ASSURANCE 
The quality of the vaccine product will be determined and guaranteed by strict adherence 
to the Standard Operating Procedure (SOP) for DC Vaccine Production following Good 
Manufacturing (GMP) and Good Laboratory Processing (GLP).  
13.0 PUBLICATION POLICY  
Results of this clinical study may be presented and/or published in National Meetings 
and/or peer-reviewed medical or scientific journals, partially or completely.  Patient’s 
personal data will remain anonymous during such presentations/publications and integrity 
of data preserved and guaranteed during the dissemination process. 
14.0 DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS, DATA 
HANDLING, AND RECORD KEEPING AND RETENTION OF STUDY 
DOCUMENTS 
Only the Study Chair, PI and Kiromic’s Clinical Research personnel may have access to 
the study source data and documents. Data will be handled exclusively by the Study 
Chair, PI, designated Clinical Research personnel and/or an officially designated person 
or persons such as one of the study sub-investigators and members of the ICSRB. Data 
will be handled under strict confidentiality and kept in a secure place at Kiromic. Only 
the Study Chair, PI, designated Clinical Research personnel and members of the ICSRB 
may have access to the study data, including patient information and study outcomes. 
Study documents will be retained at Kiromic for at least 5 years following completion 
and closure of the study. 
 
 

 
 
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APPENDIX 1: STUDY CALENDAR 
 
 
  
 
 
 
 
 
 
Study calendar is designed 
to track the administration 
and application of the study 
protocol parameters and 
may adjusted as logistically 
needed as allowed protocol 
variances.  
 
 
 
PROCEDURE 
 
 
-28 
-14 
-7 
1 
3 
8 
10 
15 
17 
22 
45 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
Documentation of confirmed 
refractory disease 
X 
 
 
 
 
 
 
 
 
 
 
Confirm completion of 
salvage therapy > 3wks prior 
to vaccination 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
Birth Control agreement 
X 
 
 
 
 
 
 
 
 
 
 
Evaluation of disease status 
X 
 
 
 
 
 
 
 
 
 
 
TAPA expression 
X 
 
 
 
 
 
 
 
 
 
 
Infectious Disease history 
evaluation (HIV, Hepatitis A, 
B,or C) 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
History & Physical 
X 
 
 
X  
X 
 
X 
 
X 
X 
Karnofsky Performance 
Status 
X 
 
 
X  
X 
 
X 
 
X 
  
X 
Concomitant Medications 
X 
 
 
 
 
 
 
 
 
 
 
CBC with diff 
X 
 
 
X  
X 
 
X 
 
X 
X 
CMP 
X 
 
 
X  
X 
 
X 
 
X 
X 
Phlebotomy/Leukapheresis 
 
X 
 
 
 
 
 
 
 
 
 
Immune Assays 
 
 
X 
 
 
 
 
 
 
X 
X 
DTH skin test 
 
 
X 
 
 
 
 
 
 
X 
X 
Oral Cyclophosphamide Max 
100mg/day x 5 days 
 
 
X 
 
X 
 
X 
 
 
 
 
Topical Imiquimod  
 
 
 
X  
X 
 
X 
 
 
 
TAPA-pulsed DC Vaccine 
 
 
 
X  
X 
 
X 
 
 
 
Dose limiting toxicity 
assessment 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 

 
 
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APPENDIX 2: KARNOFSKY PERFORMANCE STATUS SCALE 
 
DEFINITIONS 
RATING (%) 
CRITERIA 
 
Able to carry on normal activity and to 
work; No special care needed. 
100 
 
Normal no complaints; no evidence of disease 
 
Unable to work; able to live at normal 
home and care for most personal needs; 
varying amount of assistance needed.  
90 
 
Able to carry on normal activity; Minor signs or 
symptoms of disease. 
 
80 
Normal activity with efforts; some signs or 
symptoms of disease 
 
Unable to work; able to live at normal 
home and care for most personal needs; 
varying amount of assistance needed. 
70 
 
Cares for self; unable to carry on activity or to do 
active work.   
 
60 
 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
 
 
50 
  
Requires considerable assistance and frequent 
medical care. 
 
 
Unable to care for self; Requires 
equivalent of institutional or hospital 
care; diseases may be progressing 
rapidly.  
40 
 
Disabled; requires special care and assistance 
 
 
30 
 
Severely disabled; hospital admission is indicated 
although death not imminent. 
 
 
20 
 
Very sick; hospital admission necessary; Active 
supportive treatment necessary. 
 
 
10 
Moribund; fatal processes progressing rapidly. 
 
0 
Dead 
 
 
 

 
 
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APPENDIX 3: RESPONSE CRITERIA 
Immune-Related Response Criteria (irRC) (73) 
Baseline tumor assessment is determined by the sum of the products of the two largest 
perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions 
and five cutaneous index lesions) is calculated.  
At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions 
(≥ 5 × 5 mm; up to 5 new lesions per organ) are added together to provide the total tumor burden: 
Tumor Burden = SPD (index) lesions + SPD (new) lesions 
Time-point response assessment using irRC. Percentage changes in tumor burden per 
assessment time point describe the size and growth kinetics of both conventional and new, 
measurable lesions as they appear.  
At each tumor assessment, the response in index and new, measurable lesions is defined based on 
the change in tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed 
relative to baseline measurements (i.e., the SPD of all index lesions at screening). 
Overall response using the irRC 
The overall response according to the irRCis derived from time-point response assessments (based 
on tumor burden) as follows: 
• irCR: 
complete disappearance of all lesions (whether measurable or not, and no new 
lesions) confirmation by a repeat, consecutive assessment no less than 4 wk from 
the date first documented 
• irPR:  
decrease in tumor burden ≥50%relative to baseline confirmed by a consecutive 
assessment at least 4 wk after first documentation 
• irSD:  
not meeting criteria for irCR or irPR, in absence of irPD 
• irPD:  
increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden) 
confirmation by a repeat, consecutive assessment no less than 4 wk from the date 
first documented 
 
 

 
 
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Derivation of irRC overall responses 
MEASURABLE RESPONSE 
NONMEASURABLE RESPONSE 
OVERALL RESPONSE 
Index and new, measurable 
lesions (tumor burden), *% 
Non-Index lesions 
New, nonmeasurable 
lesions 
Using irRC 
↓100 
Absent 
Absent 
irCR† 
↓100 
Stable 
Any 
irPR† 
↓100 
Unequivocal progression 
Any 
irPR† 
↓≥50 
Absent/Stable 
Any 
irPR† 
↓≥50 
Unequivocal progression 
Any 
irPR† 
↓<50 to <25↑ 
Absent/Stable 
Any 
irSD 
↓<50 to <25↑ 
Unequivocal progression 
Any 
irSD 
≥25? 
Any 
Any 
irPD† 
*Decreases assessed relative to baseline, including measurable lesions only (>5 × 5 mm). 
†Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 weeks 
apart. 
Patients are considered to have irPR or irSD even if new lesions were present, as long as they met 
the respective thresholds of response as described above.   
Patients are not considered to have irPD if new lesions were present and the tumor burden of all 
lesions did not increase by ≥25%.   
In contrast to irCR, irPR, and irPD, a response of irSD does not require confirmation.  
It is important to note that irCR, irPR, and irSD include all patients with CR, PR, or SD by WHO 
criteria as well as those patients that shift to these irRC categories from WHO PD. 
Patients with irSD, particularly those with slow-declining tumor burden ≥25% from baseline at 
the last tumor assessment, are considered clinically meaningful because they show an objectively 
measurable reduction in tumor burden without reaching the 50% threshold that defines irPR.  
If a patient is classified as having irPD at a post-baseline tumor assessment, then confirmation of 
irPD by a second scan in the absence of rapid clinical deterioration is required. The definition of 
confirmation of progression represents an increase in tumor burden ≥25% compared with the 
nadir at two consecutive time points at least 4 wk apart. It is recommended that this be done at 
the discretion of the investigator because follow-up with observation alone may not be 
appropriate for patients with a rapid decline in performance status.  
Confirmation of irPD allows for the capture of all observed responses using the irRC, as most of 
these late responding patients have a trend toward response within 4 wk after initial irPD. 
Whereas WHO criteria consider any new measurable lesion to indicate PD, determination of 
immune-related best overall response (irBOR) is based on changes in total tumor burden from 
the baseline (nadir, for irPD) tumor assessment, regardless of any initial increase in baseline 
lesions or the appearance of new lesions. 
Wolchok,J, Hoos A, O'Day S, et al. Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria.  
Clin Cancer Res 15(23):7412–20, 2009 

 
 
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APPENDIX 4: NCI CTCAE V4.0 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.04_20100-06-14_QuickReference_8.5x11.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX 5: ADVERSE EVENT LOG 
STUDY TITLE 
 
SITE  
 
Principal Investigator (PI) 
 
Patient Number 
 
Patient Initials 
 
  
Has the participant had any AE during this study?   Yes     No 
 If Yes, how many? _________ 
 
 
 
 
 
                Dates: ______________________________ 
______________________ 
_____________  
_____________________  
____________ 
Clinician Name 
 
 
Clinician Initials  
 Clinician Signature 
 
Date 
 
 
______________________ 
_____________  
_____________________  
____________ 
PI Name  
 
 
PI Initials 
 
 PI Signature 
 
 
Date 
 
ADVERSE EVENT 
START DATE/TIME 
STOP DATE/TIME 
 
 
Brief Summary: 
 
 
Severity 
Relation to Study 
Drug 
Action taken with 
Investigational drug 
Corrective Action  
Outcome 
Expected 
Serious 
1= Mild 
 
2= Moderate 
 
3= Severe 
 
4= Life 
Threatening 
1= Definitely 
 
2= Possibly 
 
3= Not related 
 
4= Unknown 
1= None 
 
2= Discontinued 
permanently 
 
3= Discontinued 
temporarily 
 
4= Reduced Dose 
 
5= Increased Dose 
 
6= Delayed Dose 
1=Remedial Therapy 
(Pharmacologic) 
 
2= Remedial Therapy 
(Non pharmacologic) 
 
3=Hospitalization 
 
4=Medication 
1= Resolved 
 
2= Resolved with 
sequel 
 
3= Not resolved 
 
4= Residual 
effects present 
 
5= Death 
1=Yes 
 
2=No 
1=Yes 
 
2=No 
 

 
 
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