Induction of Antitumor Response in Melanoma Patients Using the Antimicrobial Peptide LL37
Phase: PHASE1
Conditions: Melanoma
Sponsor: M.D. Anderson Cancer Center

LL37: 2013-0422 
01/04/2017 
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Version 8 
M.D. ANDERSON CANCER CENTER 
 
 
 
 
 
 
 
 
2013-0422: INDUCTION OF ANTITUMOR RESPONSE IN 
MELANOMA PATIENTS USING THE ANTIMICROBIAL PEPTIDE 
LL37 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR 
 
Rodabe N. Amaria, MD 
 
 
 
CO-INVESTIGATORS 
 
Patrick Hwu, MD Professor and Chair 
Richard Royal, MD 
Wen-Jen Hwu, MD, PhD  
Sapna Patel, MD 
Michael Davies, MD, PhD 
Scott Woodman, MD, PhD 
Adi Diab, MD 
Isabella Glitza, MD 
Hussein Tawbi, MD 
Michael Wong, MD

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Version 8 
M.D. ANDERSON CANCER CENTER 
 
 
 
 
 
Table of Contents 
Abstract 
1 
1. Objectives 
1 
2. Background and Rationale 
2 
3. Clinical Pharmacology 
9 
4. Eligibility Assessment and Enrollment 
9 
5. Treatment Plan 
12 
6. Evaluation During Study 
13 
7. Evaluation of Toxicity 
15 
8. Criteria for Response 
20 
9. Criteria for Removal from the Study 
23 
10. Statistical Consideration and Data Analysis 
24 
11. Data Entry and Protocol Management 
25 
12. Administrative Procedures 
25 
13. References 
26 

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Abstract 
 
Tumors are potentially immunogenic, however they fail to spontaneously induce immune 
responses capable of rejecting tumors. A major reason for this is that the tumor 
microenvironment lacks adequate innate immune activation required to initiate strong adaptive 
antitumor immunity. Plasmacytoid dendritic cells (pDCs) are highly specialized components of 
the innate immune system that are capable of sensing microbial nucleic acids via intracellular 
Toll-like receptors. During viral infection, pDCs accumulate in infected tissues and are 
activated by viral nucleic acids to produce large amounts of type I interferons (IFNs) and 
generate protective immunity against the virus by activating myeloid dendritic cells, T cells, and 
natural killer cells. Tumors also contain pDCs but do not provide molecular signals to activate 
pDCs, although tumors contain self-DNA released in the extracellular environment at high 
concentrations as a result of increased tumor cell turnover. pDCs, though activated by viral 
nucleic acids, are normally not able to sense tumor-derived DNA and thus are unable to initiate 
strong innate anti-tumor immune responses. We recently found that pDCs can, in fact, sense 
and respond to self-DNA when combined with an endogenous peptide called LL37. LL37 can 
bind to self-DNA fragments released by dying cells to form aggregates and condensed 
structures that are delivered to and retained within early endosomes of pDCs. In these 
intracellular compartments, LL37/self-DNA can interact with Toll-like receptor 9 to trigger  
robust type I IFN production similarly to viral DNA. Because tumors release large amounts of 
self-DNA and contain pDCs but do not express LL37, our hypothesis for the proposed phase 
I/II outcome-adaptive Bayesian dose finding clinical trial described herein is that exogenous 
LL37 can be used to target tumor-derived self-DNA and convert it into a “danger signal” that 
triggers pDC activation and type I IFN production at the tumor site in patients with melanoma. 
This then induces T-cell-mediated immunity against melanoma by using the same mechanism 
by which anti-viral-immune responses are induced. 
 
 
1. 
Objectives 
 
1.1 
Primary Objective 
 
To determine the optimal biologic dosing of LL37 based on toxicity and efficacy. 
 
1. 2 
Secondary Objectives 
 
To evaluate antitumor immune responses and clinical efficacy of intra-tumoral 
injection of LL37 in patients with melanoma. 
 
2. 
Background and Rationale 
 
 
2.1 
Natural anti-tumor immune responses are often weak compared with antiviral 
immune responses 
 
The notion of whether the immune system is capable of recognizing, responding to, 
and eradicating established tumors was at one time a rather contentious and 

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controversial issue 1, 2.  However, much evidence has accumulated over the past two 
decades, both in humans and in mouse models and at the cellular and molecular 
level, to establish that immune cells can play an important role in inducing  
successful cancer regression 3, 4. Multiple studies using different tumor models have 
shown that administration of immune cytokines, specific vaccines, and adoptive 
transfer of immune cells can all lead to effective tumor eradication in the appropriate 
setting 5-7. Nonetheless, it is true that all of these treatments rely on specific immune 
interventions for their success. The generation of effective natural immunity against 
established tumors is likely to be a very infrequent event, as evidenced by the 
clinical manifestation of tumors in non-immunocompromised hosts and by the fact 
that spontaneous regressions are very rarely observed. 
 
By contrast, the natural generation of effective immunity against viral infections 
remains the rule rather than the exception. Multiple studies have demonstrated that 
viral infections frequently lead to the spontaneous generation of strong immune 
responses that are often not only capable of inducing viral clearance, but also in 
generating long-lived memory responses capable of protecting the host against re- 
infection 8-10.  In the past ten years, a number of seminal research studies have shed 
light on why viruses and other pathogens can elicit such potent and effective natural 
immune responses. We believe that harnessing and adapting the mechanisms used 
by pathogens to induce effective specific immunity represents a very promising 
approach to improving specific antitumor immune responses. 
 
 
2.2 
Activation of innate immunity is critical for the generation of effective 
adaptive immune responses 
 
 
Effective antiviral immune responses are initiated through activation of innate 
immune cells, including NK cells, conventional myeloid dendritic cells (mDCs), and 
plasmacytoid dendritic cells (pDCs), by specific TLR ligands 11-13.  Activation of 
innate immunity induces the production of proinflammatory cytokines which can 
directly activate cells important for the initiation of adaptive immune responses.  
Type I interferons (IFNs) and tumor necrosis factor (TNF-β), for example, are potent 
inducers of mDC maturation, inducing upregulation of major histocompatibility 
complex (MHC) and costimulatory molecules as well as production of IL-12, all of 
which are important for the priming of naïve T cells 14,15. In addition, the activation of 
NK cells by pDC, cytokines and TLR ligands may lead to increased lysis of virally- 
infected cells or tumors which can provide antigen to mDCs for presentation to T 
cells. Activation of innate immunity is important not only for the generation of 
antigen-specific T-cells, but also to induce inflammation at the pathogen site which 
leads to enhanced migration of antigen-specific T-cells to the infected tissue. 
 
 
2.3 
Plasmacytoid DCs represent a critical link between innate and adaptive 
immunity 

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As the major producer of type I IFNs (represented by IFN-α and IFN-β), pDCs 
represent one of the most important links between innate and adaptive immunity 16- 
20. Upon triggering of TLR7 or TLR9 by virus, pDCs rapidly produce large amounts of 
Type I IFNs, activate a variety of immune cells such as B cells, natural killer (NK) 
cells and macrophages, and differentiate into antigen presenting cells (APCs) to 
induce antigen-specific T cell responses 21. Both mDCs and NK cell activation can 
               -/- mDCs are defective in 
the ability to adequately respond to viral infections 22, suggesting that interferon- 
producing pDCs may be critical for the activation of mDCs and subsequent 
development of adaptive immunity. 
 
 
2.4 
Cancer vaccines have significant potential to generate anti-tumor responses, 
but require considerable optimization 
 
The identification of tumor antigens recognized by T-cells has allowed the 
development of rational cancer vaccine strategies.  Current evidence suggests that 
cancer vaccines have the ability to increase the levels of circulating T-cells capable 
of recognizing tumor antigens.  However, this has not led to significant tumor 
regressions in patients.  For example, an analysis of the response rate in over 500 
patients with metastatic melanoma treated with vaccines was under 3% 23.  Our 
hypothesis is that this is due to inadequate activation of innate immunity at the site of 
immunization as well as at the tumor site itself. Lack of adequate inflammation at  
the vaccine site may lead to suboptimal T-cell priming, while equally important; the 
lack of inflammation at the tumor site may lead to inefficient migration of T-cells back 
to the tumor. 
 
 
2.5 
Plasmacytoid dendritic cells and myeloid dendritic cells synergize in their 
ability to generate antigen specific immune reactions, resulting in enhanced 
antitumor responses in vivo 
 
We hypothesized that by their capacity to activate innate immunity, pDCs would 
potentiate the function of mDCs when used in combination. Indeed, when purified 
murine pDCs and mDCs were co-cultured in the presence of antigen and a TLR 
activation stimulus, such as CpG, followed by in vivo administration, antigen-specific 
T-cell levels were higher than with the administration of either DC subset alone 
(Figure 1). Since the total number of DCs was kept constant for all groups, the 

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600600 
50500 
no pepeptide 
OV 
A 
pep
e 
pti 
de 
400400 
300300 
Tumor size 
# of IFN-g secreting cells/2 x105 
% 
 
no peptide 
OVA peptide 
 
 
 
 
0 
mDC 
+
+ 
- 
- 
+ 
+ 
- 
pDC 
- 
- 
+ 
+ 
+ 
+ 
- 
CpG 
- 
+ 
- 
+ 
- 
+ 
- 
 
 
 
 
 
Figure 1. Immunization with a  combination of 
TLR9-activated pDC plus mDC significantly 
enhances antigen-specific CTL responses. 
Mice were immunized s.c. with purified pDC, 
mDC, or a combination of pDC and mDC (1:1) 
which were first co-cultured for 4 hours with  CpG 
and OVA257-264 peptide (the total number of DCs 
injected were kept at the same level for all 
groups). Seven days after immunization, mice 
were bled and PBL were isolated. Ag-specific IFN- 
γ production by immune cells was assessed by 
ELISPOT assay upon in vitro restimulation with or 
without OVA peptide. ELISPOT picture represents 
duplicate wells in each immunized group in the 
presence of OVA peptide stimulation. 
 
interaction between pDC and mDC in their ability to stimulate T-cells was 
synergistic and not simply additive. 
 
Importantly, tumor reduction was also enhanced when mice were treated with the 
combination of activated, antigen-pulsed pDC and mDC compared to either DC 
subset alone (Figure 2).  Treatment of tumors with a combination of pDC and 
mDC resulted in mice with both smaller tumors (Figure 2A) and enhanced 
survival (Figure 2B). 
 
 
 
A 
 
200 
 
150 
 
 
 
50 
 
00 
 
B 
 
1100 
0 
0 80 
 
860 
* 
* 
* 
640 
 
420 
 
2 0 
 
 
 
 
 
 
 
* 
* 
 
200 
 
 
 
mDC/OVA 
pDC/OVA 
(mDC + pDC)/OVA 
pDC)/OVA 
p(mDDCC)/O+VpADC)/NP 
(mDC + 
p(n(mDoDCtrC)e/Na+tPment 
pnDoCtr)e/NatPment 
no treatment 
Figure 2. Immunization with a 
combination 
of 
TLR9-activated 
pDC 
plus 
mDC 
improves 
therapeutic 
efficacy 
against 
tumor. Mice were inoculated s.c. 
with E.G7 (OVA+) tumor cells. Four 
days later, the tumor-bearing mice 
were immunized s.c. with TLR9- 
activated, OVA peptide-pulsed pDCs 
or mDCs alone, or a combination of 
pDCs plus mDCs, as described in 
Figure  5.  Tumor  growth  (A)  and 
0 
10 
20 
30 
Days after treatment 
0 
20 
40 15060 
Days after treatment 
mouse survival (B) was monitored.  ( 
* =Ps<0.05). 

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Figure 3. Self-DNA coupled with LL37 triggers 
pDCs via TLR9. IFN-α produced by pDCs after 
stimulation with (A) LL37 plus chloroquine at 
increasing concentrations or (B) LL37, CpG-B- 
2006, or R837 after pretreatment with ODN- 
TTAGGG or a control (ctrl-ODN). (C) IFN-α4 
promoter activity of IRF7/TLR9 (solid bars)- or 
IRF7/TLR4 
(empty bars)-transfected 
HEK293 
cells measured using a luciferase assay after 
stimulation under the indicated conditions. CpG- 
2216 complexed with cationic lipids (DOTAP) was 
used as a positive control. The data in A and B 
are 
representative 
of 
four 
independent 
experiments; the error bars represent the SD of 
triplicate wells. The data in C were statistically 
analyzed using an unpaired two-tailed Student t- 
test and presented as the mean ± the standard 
error 
of 
the 
mean 
for 
five 
independent 
experiments. *p=0.01; **p=0.003. 
 
 
 
 
2.6 Self-DNA Coupled with LL37 Triggers TLR9 
 
Because pDCs sense DNA through TLR9 24, we examined TLR9 to determine whether 
it is involved in the recognition of the LL37/self-DNA complex by pDCs. Chloroquine, 
which blocks endosomal TLR signaling, potently inhibited the IFN-α expression induced 
by LL37/DNA (Figure 3A). To specifically inhibit TLR9 in pDC, we used short 
oligonucleotides (ODN-TTAGGG) that block type I IFN induction by CpGs (TLR9 
agonists) but not by imiquimod (R837; TLR7 agonist) (Figure 3B). Pretreatment of 
pDCs with ODN-TTAGGG specifically inhibited IFN-α induction by LL37/DNA. We 
confirmed TLR9-mediated recognition of LL37/DNA by showing that the LL37/DNA 
complex activated the IFN-α4 promoter in IRF7/TLR9-transduced HEK293 cells but not 
in HEK293 cells expressing an irrelevant TLR (Figure 3C). As in pDC cultures, the 
LL37/DNA complex but not DNA alone activated TLR9-transduced cells. However, in 
contrast with pDC cultures, LL37 alone was unable to induce activation of TLR9- 
transduced cells, which is consistent with the absence of cell death in these cultures 
and hence lack of DNA release. Taken together, these data demonstrate that in 
complexes with LL37, self-DNA can activate pDCs through TLR9 25. 
 
 
2.7 
Human Melanomas Contain pDCs in the Vicinity of Dying Tumor Cells but Do Not 
Express LL37 
 
Human blood pDCs can be identified according to their unique surface expression 
profiles lacking common lineage markers for T, B, NK cells and monocytes with 

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Figure 4. Melanoma metastases contain pDCs and dying tumor cells but do not 
express LL37. (A) pDCs of -HLADR+ CD123+ lineage in mononuclear cell suspensions 
of a subcutaneous melanoma metastasis. Tumor pDCs co-exist with dying 7-AAD+ 
tumor cells. (B) Percentage of pDCs among mononuclear cells in melanoma 
metastases in four independent specimens measured as described in A. (C) pDC 
identification using flow cytometry (left panel) and immunohistochemistry for BDCA-2. 
 
 
 
exions obtained from DCs of Hs 4A and 4BpDCs siells ofHLADR+ CD123+ lineage 
(Figure 4C). Immunohistochemical analysis of BDCA-2 confirmed that substantial 
numbers of pDCs can infiltrate the tumor microenvironment of human melanoma 
metastases. Tumor-infiltrating pDCs had nonactivated phenotypes as described 
previously 35 and were able to produce type I IFNs in response to CpGs as demonstrated 
by stimulation of tumor-derived mononuclear cell suspensions (data not shown). As 
aggressively growing tumors, melanomas are typically characterized by high numbers of 
dying tumor cells. This phenomenon is well known to pathologists in particular because 
the high degree of cell death makes immunohistological analysis of tumor specimens 
difficult to interpret26.  Using flow cytometry, we indeed found considerable numbers of 
dead tumor cells identified according to their typical large size with high forward/side 
scatter and staining for 7-AAD. The presence of dying tumor cells suggests the presence 
of self-DNA released into the extracellular tissue compartment. 

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Tumor size 
 
Interestingly, we typically found pDCs in areas of tumors where structural integrity is lost 
because of tumor cell death (Figure 4C). 
 
 
2.8 
LL37 Can Bind Self-DNA Released by Dying Tumor Cells 
 
LL37 has the ability to bind to DNA and protect it from nuclease degradation 25, 27. To 
determine the ability of LL37 to bind to and protect self-DNA released by dying tumor 
cells from nuclease degradation, we generated apoptotic melanoma cells in the 
presence or absence of LL37 and measured the DNA content in culture supernatants 
using electrophoresis. We confirmed the presence of apoptosis induction by using 
Annexin V plus propidium iodide staining and using electrophoresis, we detected DNA 
exclusively in supernatants of irradiated melanoma cells cultured with LL37 (data not 
shown). These results indicated that irradiated melanoma cells release self-DNA that is 
bound to LL37 and protected by LL37. 
 
 
2.9 
Intratumoral Injection of LL37 Elicits Local Antitumor Activity 
 
We inoculated 3 x 105 B16 melanoma cells into shaved flanks of C57BL/6 mice. We 
allowed the resulting tumors to grow for 7 days. On day 7, we injected tumors with a 
single dose of LL37 (20 μmol) or injected them with saline as a control. We monitored 
tumor size using a caliper and estimated tumor volume using the formula π/6 x length x 
width2. We stopped the experiment 12 days after injection because all of the mice in the 
control group had died or their tumors had reached at least 20 mm in maximal diameter. 
We found that a single intratumoral injection of LL37 significantly delayed the growth of 
established B16 tumors (Figure 5). Thus, intratumoral LL37 injection induces potent 
antitumor activity in melanomas. 
 
 
 
600 
PBS (control injection i.t.) 
500 
400 
Single LL37 injection i.t. 
300 
200 
100 
0 
0 
5 
7 
9 
11 
13 
15 
LL37 injection 
Days after B16 inoculation 
17 
19 
 
 
2.10 Vaccination with LL37 plus Dying Tumor 
Cells Elicits Systemic Antitumor Activity 
 
Figure 
5. Single 
intratumoral 
injection 
of LL37 
delays growth of pre-established B16 tumors. 
Mice bearing 7- day subcutaneous B16/F10 melanomas 
were injected with 20 µmol of LL37. PBS injections were 
performed as controls. Tumor size was monitored using 
caliper every second day. The data represent the mean for 
four mice per group. i.t., intratumoral. 

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Figure 6. Single vaccination with LL37 plus 
irradiated B16 cells expressing OVA delays the 
growth of pre-established B16-OVA tumors. Mice 
bearing 
7-day 
subcutaneous 
B16 
melanomas 
transfected with a gene encoding OVA (B16-OVA) 
were vaccinated subcutaneously with LL37 alone, 
irradiated B16-OVA tumor cells (iB16-OVA), irradiated 
B16-OVA tumor cells mixed with 20 µmol of CpG-2216 
(iB16-OVA+CpG), or irradiated B16-OVA tumor cells 
with 20 µmol of LL37 (iB16-OVA+LL37). Tumor size 
was monitored using a caliper every other day. The 
data represent the mean for four mice per group. 
 
 
 
We performed vaccine studies using the B16 model of melanoma. B16 cells can be 
transfected with ovalbumin (OVA) to produce an immunogen that allows easy tracking of 
antitumor immune responses. We subcutaneously implanted 3 x 105 B16-OVA cells in the 
flanks of C57BL/6 mice and allowed them to grow. Seven days later, we gave the mice single 
subcutaneous injections of LL37 mixed with irradiated B16-OVA cells. Control injections 
included LL37 alone, irradiated B16-OVA cells alone, and irradiated B16-OVA cells mixed with 
the synthetic TLR9 agonist CpG. A detailed method for the generation of these vaccines is 
described below in Research Design and Methods. We monitored the sizes of the resulting 
tumors using a caliper and estimated the tumor volumes using the formula π/6 x length x 
width2 as described previously. We stopped the experiment 10 days after the injections 
because all of the mice in the control group had died or had tumors that were at least 20 mm in 
maximal diameter. Vaccination with LL37 plus irradiated tumor cells significantly delayed the 
growth of 7-day established B16 tumors more than the control groups and more than the mice 
that received irradiated B16-OVA cells mixed with CpG (Figure 6). These findings indicate that 
vaccination with LL37+dying tumor cells elicit potent systemic antitumor activity. LL37 appears 
to be more potent than CpG, which is among the most potent adjuvantscurrently tested in 
clinical vaccination trials 35. We performed these experiments using CpG-2216, which is the 
most potent CpG sequence for inducing type I IFNs in both murine and human pDCs 28. 
 
Having demonstrated that LL37, which is capable of stimulating innate immunity by activating 
pDCs and inducing antitumor immune response, we propose to evaluate this peptide in 
patients by injecting LL37 into accessible tumor sites followed by evaluations of tumor size, 
blood samples, and biopsies of injected and non-injected tumors. 
 
2.11 Rationale for Current Protocol 
 
In this study, we will inject melanoma tumor deposits with LL37 in order to activate the 
innate immune response at the tumor site. We hypothesize that this will lead to a strong 
systemic T-cell response resulting in immune activation and tumor regression at LL37 
injected as well as non-injected sites. The primary objective will be to ascertain the 
optimal biologic dose of LL37 which will be defined based upon toxicity and efficacy 
 
We anticipate that these studies may lead to principles in cancer immunotherapy that 
may be widely applicable to the treatment of melanoma as well as other cancer types. 

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3. 
Clinical Pharmacology 
 
3.1 
LL37 Peptide Preparation and Administration 
 
Synthetic LL37 will be manufactured in GMP conditions and supplied as a 
lyophilized bulk powder by Bachem Americas. The lyophilized powder will be 
reconstituted to a concentration of 8 mg/mL in sterile saline and stored frozen in 
aliquots of at -20°C. The peptide solution will be thawed and diluted as required 
in sterile saline to achieve peptide concentrations of 8 mg/mL (2000 μg/250 μL) 
or 4 mg/mL (1000 μg/250 μL) or 2 mg/mL (500 μg/250 μL) or 1 mg/mL (250 
μg/250 μL). Peptide solution will be prepared in P14 CTL/GMP laboratory by 
trained personnel. The peptide solution will be prepared from the bulk LL37 
received from Bachem Americas according to an approved SOP. The solution 
will be vialed and the lot will be tested per the SOP. Analytical testing is 
performed by the contracted testing laboratory SGS MScan per GMP peptide 
specific procedures and a QA reviewed/approved report is provided to the MD 
Anderson GMP. The MD Anderson GMP will prepare a CoA and if all test 
specifications are met, the lot will be released and sent to investigational 
pharmacy. 
 
Since it is assumed that the average size of a melanoma nodule is approximately 
1cm3 which is equivalent to 1mL, use of a vialed peptide solution at 
2000µg/250µL would produce a final concentration of 2000µg/250 µL injected 
into the tumor. Similar mathematics is utilized for all dose levels and injection of 
250µL of LL37 administered into tumor sites will achieve concentrations of 250, 
500, 1000, or 2000 µg/tumor. Up to four lesions will be treated per patient. 
 
3.2 
Dose Justification 
 
In our murine studies we injected 100 µg into 0.1-0.2 cm3 tumors. Assuming that 
tumors are a self-contained mass in which the injected peptide will diffuse, we 
hypothesize concentrations of 500-1,000 µg/ml are in the range that is needed 
for pDC activation and antitumor function. This range is also close to the levels 
seen in psoriasis patients (mean 1,520 µg/ml), in which robust pDC activation is 
seen29. Therefore, in the clinical trial we propose to inject 250, 500, 1,000, or 
2,000 µg of LL37 peptide into tumors. Assuming that the average size of injected 
human melanoma nodules is 1cm3 (= 1ml) the concentrations in the tumors will 
be 250, 500, 1,000 or 2,000 µg/ml. We estimate that these levels should be well 
tolerated by patients based on the murine data and levels found in psoriasis 
patients. 

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4. 
Eligibility Assessment and Enrollment 
 
4.1 
Inclusion Criteria 
 
 
 
4.1.1 Patients with histologically documented metastatic melanoma with at least 
3 cutaneous lesions measuring over 5mm diameter. At least two lesions 
must be at least 10mm in diameter to serve as the injected disease. At 
least one other lesion measuring at least 5mm in diameter may serve as 
the non-injected lesion that will be measurable disease. Patients will have 
stage IIIB or IIIC (in-transit lesions with or without nodal metastases) or 
stage IV M1A disease with cutaneous or nodal lesions assessable for 
administration of LL37. Patients are only eligible if their melanoma 
deposits are not amenable to complete surgical excision. Skin lesions that 
are 5mm or greater are deemed measurable however lesions that are at 
least 10mm in diameter will be preferentially utilized for LL37 injection. 
 
4.1.2 Age greater than or equal to 18 years. 
 
4.1.3 Clinical performance status of ECOG 0 – 2 within 30 days of signing 
informed consent. 
 
 
 
4.1.4 Total bilirubin less than or equal to 2.0 mg/dl, except in patients with 
Gilbert’s Syndrome who must have a total bilirubin less than 3.0 mg/dl. 
 
4.1.5 Platelet count greater than or equal to 100,000/mm3 
 
4.1.6 WBC >3000/mm3 
 
4.1.7 Serum ALT and AST less than three times the upper limit of normal 
 
4.1.8 Serum creatinine < 2.0 mg/dl 
 
4.1.9 Seronegative for HIV antibody 
 
4.1.10 Patients with a negative pregnancy test (urine or serum) must be 
documented within 28 days of of starting treatment for women of 
childbearing potential (WOCBP). A WOCBP has not undergone a 
hysterectomy or who has not been naturally postmenopausal for at least 
12 consecutive months (i.e. who has not had menses at any time in the 
preceding 12 consecutive months). 
 
4.1.11 Unless surgically sterile by bilateral tubal ligation or vasectomy of 
partner(s), the patient agrees to continue to use a barrier method of 
contraception throughout the study such as:  condom, diaphragm, 

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hormonal, IUD, or sponge plus spermicide. Abstinence is an acceptable 
form of birth control. 
 
4.1.12 Patients must consent for protocol PA13-0291 for potential immunologic 
 
evaluations on biopsy specimens. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Active autoimmune disease requiring disease modifying therapy. 
 
4.2.2 Concurrent systemic steroid therapy. 
 
4.2.3 Any form of active primary or secondary immunodeficiency. 
4.2.4 Prior malignancy except the following: adequately treated basal cell or 
squamous cell skin cancer, in-situ cervical cancer, thyroid cancer (except 
anaplastic) or any cancer from which the patient has been disease-free for 
2 years. 
 
4.2.5 History of immunization with LL37. 
 
4.2.6 Active systemic infections requiring intravenous antibiotics. 
 
4.2.7 Prior systemic therapy, radiation therapy, or surgery within 28 
days of starting study treatment 
 
4.2.8 Patients who are pregnant or nursing. 
 
4.3 
Pretreatment Evaluation 
 
At the screening visit, patients will be assessed for study eligibility. All patients 
must sign an informed consent form and a negative pregnancy test (urine or 
serum) must be documented for women of childbearing potential before 
enrollment and being registered in CORE/PDMS.  Consent will be obtained 
within 28 days of therapy initiation. 
 
The following baseline studies must be completed within 28 days of treatment 
initiation: 
 
4.3.1 Complete history, demographics, concurrent medication usage and 
physical examination including vital signs, height, weight, noting in detail 
the exact size and location of any lesions that exist will be performed. 
 
4.3.2 Chemistries to include serum electrolytes, BUN, creatinine, glucose, 
albumin, alkaline phosphatase, ALT, AST, LDH, calcium, and total 
bilirubin. 
 
4.3.3 CBC, differential, PT/PTT, and platelet count will be performed. 

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Dose Level 
LL37 
1 (starting dose) 
250 µg/tumor per week 
2 
500 µg/tumor per week 
3 
1000 µg/tumor per week 
4.3.4 β-HCG pregnancy test (urine or serum) on all women of childbearing 
potential will be performed. 
 
4.3.5 EKG. 
 
4.3.6 HIV serology. 
 
4.3.7 Baseline radiological studies to evaluate the status of disease (CT scans 
of chest, abdomen, pelvis: MRI/CT of brain) to evaluate the status of 
disease. Ultrasound or CT of area of in transit lesions is required. 
 
 
 
The following pre-treatment studies must be completed within 7 days of 
treatment initiation: 
 
4.3.8 Medical photography and measurements of in-transit lesions and/or 
cutaneous lesions. 
 
4.3.9 Baseline adverse event recording, physical exam and concurrent 
medication usage will be documented 
 
4.3.10 Baseline biopsy of tumor site to be injected with LL37 
 
 
 
4.3.11 If patient agrees to the optional procedure, leukapheresis consisting of 
7.5-10 liter exchange lasting approximately 3 hours to obtained baseline 
immunologic sampling 
 
 
 
5. Treatment Plan 
 
5.1 
Phase I (dose escalation) Overview 
 
The dose escalation schema is listed in table 5.1. 
Table 5.1: dose escalation schema for phase I 
 
 
 
 
 
 
 
A total of 36 patients will be enrolled into the study.  Two patients will be entered 
at each dose level beginning with cohort 1 (starting dose 250 µg/tumor). The 
number of subjects at each dose level will be assigned adaptively as described in 
the Statistics Section (section 10) but to summarize, the efficacy and toxicity of 

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each dose will be monitored simultaneously and will be used to determine the 
desirability of each dose. Once two patients have been treated on the same 
dosing level, pre-treatment and 24 hour post treatment biopsies will be analyzed 
for amount of interferon alpha upregulation by RT-PCR analysis. DLT 
assessment will be done within the first two weeks of each patient’s therapy. 
Once the efficacy and toxicity data are available, the EffTox program will be 
utilized and the next cohort of patients can be assigned. 
There will be no intra-patient dose escalation above the assigned dosing. 
Dose Limiting Toxicity in a given patient is defined as: 
a. Any grade 3 or 4 non-hematologic toxicity by NCI CTCAE Version 4.03 
regardless of duration, including: 
Grade 3 skin reactions at injection sites including experiencing severe tissue 
damage or require operative intervention and Grade 3 fever 
b. Grade 3 or 4 hematologic toxicity as per the NCI CTCAE Version 4.03 
 
 
 
DLT monitoring will be done within the first two weeks of therapy.  Patients will 
discontinue administration of LL37 if they experience a DLT. 
 
LL37 will be administered intratumorally in cutaneous or subcutaneous tumors at 
least 1 cm in diameter. Patients will receive weekly intratumoral injections of 
LL37 for up to 8 weeks. The injections will be given every 7 days (+/- 48 hours). 
 
Dose administration will be delayed based on toxicities including development of 
intolerable Grade 2 toxicities with a specific focus on fevers and injection site 
reactions. Doses can be held for a maximum of 2 weeks. Protocol therapy will be 
discontinued if toxicities do not reduce to at least Grade 1 within this specified 
time. 
 
Biopsy samples of injected tumors will be obtained before the initial injection, 24 
hours (+/- 8 hours), and 4 weeks (+/- 48 hours) after the initial injection. 
Minimum biopsy sample size is a 5mm by 5mm punch biopsy performed in clinic 
by mid-level providers or attending physicians. The samples will be obtained by 
either a punch biopsy or an excisional biopsy.  Biopsy samples of distant non- 
treated tumors will be obtained at week 4 (+/- 48 hours). 
 
Peripheral blood, approximately 60 ml, will be collected before the initial injection 
and then every 2 weeks (+/- 48 hours) to assess systemic immune responses to 
tumors.  If patient agrees to the optional procedure, leukapheresis will be 
performed prior to initial treatment and at week 8 for more extensive immune 
monitoring. 

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5.2 
Study Calendar 
Pre- 
study 
(within 
28 
days of 
start) 
Pre- 
study 
(within 
7 days 
of 
start) 
Start 
(Day 1, 
week 
1) 
Day 2 
week 
18 
Week 
29 
Week 
39 
Week 
49 
Week 
59 
Week 
69 
Week 
79 
Week 
89 
Off 
study
10
 
Informed 
consent 
x 
EKG 
x 
HIV serology 
x 
Medical 
photography 
x 
x 
x 
x 
Demographics 
x 
Medical history 
x 
Concurrent 
meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical exam 
+ vitals + PS
1
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse event 
evaluation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CBC with diff 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 
chemistries
2
 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT, PTT 
x 
Β-hcg
3
 
x 
Biopsy injected 
site
4
 
x 
x 
x 
x 
Biopsy 
noninjected 
site
5
 
x 
Leukapheresis
6
 
x 
x 
Research 
blood
7
 
x 
x 
x 
x 
x 
Radiologic 
evaluations 
11
 
x 
x 
x 
Clinical tumor 
measurements 
x 
x 
x 
x 
1. 
Full physical exam including vital signs and Eastern Cooperative Group Performance Status 
2. 
Serum chemistries include: albumin, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorous, 
potassium, total protein, SGOT (AST), SPGT (ALT), sodium 
3. 
Serum or urine β-hcg test in women with child bearing potential 
4. 
If feasible, biopsy of LL37 injection site week 4 will be performed. Biopsy will only be done if there is evidence of clinical tumor 
persistence. 
5. 
If feasible, biopsy of non-LL37 injected lesion will be performed at week4. Biopsy will only be performed at week 4 if clinically 
evident tumor remains 
6. 
If patient agrees to the optional procedure, leukapheresis will be performed prior to treatment and 8 weeks (+/- 48 hours) after initial 
LL37 injection. Each leukapheresis will consist of a 7.5-10 liter exchange lasting approximately 3 hours 
7. 
Approximately 60mL of blood will be taken for research purposes including 1 10mL red top tube for serum, 1 green top tube for 
plasma and 2 20mL green top tubes for peripheral blood mononuclear cells 
8. 
24 hours +/-8 hours after initial LL37 injection. It is preferable that this biopsy site be different from the site of the initial biopsy if 
possible 
9. 
All subsequent time measurements are weekly +/- 48 hours from time of initial LL37 injection 
10. 
Off study is at time of documented progression as per the immune mediated response criteria, withdrawal of consent or significant 
noncompliance on the protocol or grade IV adverse event 
11. 
Radiologic evaluations in the form of CT scans of affected disease sites will be performed every 8 weeks (+/- 14 days) while on study. 

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6. 
Evaluation during Study 
 
6.1 
Clinical evaluation: 
 
Patients will be evaluated every week at the time of the injections for up to 8 
weeks. Physical examination, update of concurrent medications and adverse 
event recordings will be done during weekly visits prior to LL37 injections.  CBC 
with differential and serum chemistries during weekly visits for up to 8 weeks and 
when off study will be performed. Medical photography at baseline, week 4, 8 
and off study will be performed. After completion of LL37 injections, patients will 
be followed routinely in clinic for a period of one year to assess ongoing 
response to therapy. 
 
6.2 
Immunological Evaluations 
 
6.2.1 For blood and tissue studies, specimens will be collected as part of the 
protocol as specified in the Study Calendar (section 5.2), processed 
and/or stored for later analysis. 
 
6.2.2 If patient agrees to the optional procedure, leukapheresis will be utilized 
for blood collection instead of phlebotomy to obtain peripheral 
lymphocytes at two time points when feasible. Leukapheresis will be 
performed prior to treatment and 8 weeks (+/- 48 hours) after initial LL37 
injection for assessment of specific T-cell reactivity in peripheral blood. 
 
Each leukapheresis will consist of a 7.5 to 10 liter exchange lasting 
approximately 3 hours. 
 
6.3 
Biopsies 
 
 
 
Two areas will be biopsied during the course of the study including LL37 injected  
 
 
and non-injected sites. The first biopsy will be taken as a base line at any time after 
 
 
enrollment onto the trial, but prior to the first vaccination. Tumor biopsy of an  
 
 
injected site will be taken approximately 24 hours (+/- 8 hours) after initial LL37  
 
 
injection to allow for analysis of interferon alpha levels which will help inform us of 
 
 
the optimal biologic dose. At week four, biopsy of both LL37 injected and non-  
 
 
injected sites will be taken if tumor tissue is still present. Tumor biopsies may be  
 
 
taken using any biopsy method to optimize tumor yield using standard sterile  
 
 
techniques. We anticipate most biopsies will be done via a 5mm x 5mm skin punch 
 
 
biopsy performed in clinic. At least one injected or one non-injected deposit must  
 
 
not be biopsied to allow for preservation of measureable disease. Fresh tumor  
 
 
biopsies will be sent to the Immunotherapy Platform or Melcore lab. 
 
If patient agrees to the optional procedure, blood and tissue specimens 
collected in the course of this research project may be banked and provided in 
the future to investigators with IRB approved research protocols. 
 
 
 
 

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6.4 
Off study is at time of documented progression as per the immune mediated 
response criteria, withdrawal of consent or significant noncompliance on the 
protocol or grade IV adverse event. Off study procedures will include full physical 
exam, documentation of adverse events and concurrent medications, scans for 
documentation of progression, tumor biopsy, research blood, standard of care 
laboratories, medical photography and clinical tumor measurements. Off study 
procedures will be completed within 14 days of patient going off-treatment. 
Patients will be contacted by phone or clinic visit at 30 days (+7 days) from last 
drug administration for all drug-related toxicities which were present at the end of 
study. 
 
6.5 
Duration of Treatment 
 
Patients who tolerate the drug without documented evidence of progression (as 
defined by Immune Mediated Response Criteria) will be treated for eight weeks. 
After completion of all 8 sets of LL37 injections, patients will be monitored off of 
therapy with routine clinic visits and restaging scans every 8-12 weeks per the 
discretion of the treating physician. 
 
6.6  
Duration of Follow Up 
 
  
After patients are removed from the study, they will be followed every 3 months 
  
for 1 year to assess status of disease if possible. If the patient does not plan to 
  
continue to receive medical care at MDACC, they will be contacted by  
  
phone/email/letter to assess disease status. 

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6.6 
Priority of assays and quantitative parameters for analysis 
 
Tissue Type 
Parameter 
Modality 
Assay 
Quantitative 
Measurement 
Priority 
Blood 
T-cell phenotype 
Flow cytometry 
Specific antibodies 
for effector-memory 
panel and homing 
panel 
Percentage of cells 
expressing markers 
1 
T-cell cytokine production 
Luminex and 
ELISPOT 
T-cell production of 
IFN- 
 
cytokines 
Specific cytokine 
release or number of 
antigen-specific 
spots per 106 CD8+ 
(for gp100) or CD4+ 
(for MAGE-3) T cells 
2 
T cell specificity for 
melanoma antigens 
Flow cytometry 
Tetramer staining for 
MART-1, gp100, and 
tyrosinase 
Percentage of 
antigen-specific 
CD8+ (MART-1, 
gp100, tyrosinase) T 
cells 
3 
T-cell specificity for 
melanoma antigens 
(if no tetramer+ CD8+ cells 
are found) 
Overlapping 
peptide libraries 
Cytokine production 
against de novo 
antigens 
Specific cytokine 
release per 106 T 
cells 
4 
Tumor 
(LL37 treated 
and 
untreated) 
Immune cell function 
qRT-PCR 
qRT-PCR for 
cytokine gene 
expression 
Relative expression 
of cytokine genes 
compared to 
housekeeping genes 
1 
Immune cell infiltration 
IHC 
Antibodies to pDCs, 
mDCs, NK cells, and 
T cells 
Number of positive 
cells per high-power 
field 
2 
T-cell specificity and 
phenotype 
Flow cytometry 
Tetramer and T-cell 
phenotype 
antibodies 
Percentage of 
antigen-specific 
CD8+ (MART-1, 
gp100, tyrosinase) T 
cells positive for 
tetramer and other 
markers 
3 
Immune cell phenotype 
Flow cytometry 
Antibodies specific 
for pDCs, mDCs, 
and Treg (Foxp3); 
effector-memory and 
homing panel 
Percentage of cells 
expressing markers 
4 
 
7. Evaluation of Toxicity 
 
7.1 
This study will utilize the National Cancer Institute Common Terminology Criteria 
(CTC) for Adverse Events version 4.03 for toxicity and Adverse Event reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.03. 

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7.2 
Dose Limiting Toxicity in a given patient is defined as: 
b. 
Any grade 3 or 4 non-hematologic toxicity by NCI CTCAE Version 4.03 
regardless of duration including: grade 3 skin reactions at injection sites 
including experiencing severe tissue damage or require operative 
intervention and Grade 3 fever 
Grade 3 or 4 hematologic toxicity as per the NCI CTCAE Version 4.03 
regardless of duration. 
 
 
 
7.3 
Adverse event recording will occur weekly prior to LL37 injections 
 
7.4 
The principal investigator will monitor the data and toxicities to identify trends. 
The principal investigator will be responsible for revising the protocol as needed 
to maintain safety. The MD Anderson IRB will review serious adverse events as 
they are submitted. Serious adverse events will be submitted to the FDA by the 
IND Safety Project Manager in the IND Office. The principal investigator will also 
review serious adverse events and evaluate trends. Whenever a trend is 
identified, the principal investigator will determine an appropriate follow up plan. 
The investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for 
each event for all subjects enrolled on the trial. 
Prior to advancing the dose level cohort, a cohort summary will be submitted to 
the clinical research monitor. 
7.5 
Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
 
7.5.1 Death. 
 
7.5.2 A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse experience as it occurred. It does not include an 
adverse experience that, had it occurred in a more severe form, might 
have caused death. 
 
7.5.3 Inpatient hospitalization or prolongation of existing hospitalization. 
 
7.5.4 A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
 
7.5.5 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered a serious adverse drug 

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experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 
312.32).Important medical events as defined above, may also be 
considered serious adverse events. Any important medical event can and 
should be reported as an SAE if deemed appropriate by the Principal 
Investigator or the IND Sponsor, IND Office. 
 
7.5.7 All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M.D. 
Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices. Unless stated otherwise in the protocol, all SAEs, expected or 
unexpected, must be reported to the IND Office, regardless of attribution 
(within 5 working days of knowledge of the event). 
 
7.5.8 All life-threatening or fatal events, that are unexpected, and related to 
the study drug, must have a written report submitted within 24 hours (next 
working day) of knowledge of the event to the Safety Project Manager in 
the IND Office. 
 
7.5.9 Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB. 
7.5.10 Serious adverse events will be captured from the time of the first protocol- 
specific intervention,  until 30 days after the last dose of drug, unless the 
participant withdraws consent. Serious adverse events must be followed 
until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
 
7.5.11  Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 
 
7.5.12 Reporting to FDA 
 
7.5.12.1 
Serious adverse events will be forwarded to FDA by the IND 
Sponsor (Safety Project Manager IND Office) according to 
21 CFR 312.32. 

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7.5.13 It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal 
Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines and Institutional Review Board policy. 
 
 
 
Recommended Adverse Event Recording Guidelines 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Possible 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Probable 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Definitive 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
 
7.5.14 IND safety reports as required under 21CFR312.32©(1). 
 
7.5.15 Abnormal laboratory test results will be captured if intervention is required. 
 
 
 
7.5.16 Careful evaluation to ascertain the toxicity, immunologic effects and anti- 
tumor efficacy of therapy will be performed. 
 
 
 
8. 
Criteria for Response 
 
8.1 
Tumor measurements will be performed at week 0, then every 4 weeks while the 
patient remains on the study.  For visible cutaneous or palpable subcutaneous 
tumors, target sites will be assessed by measurements of tumor size on clinical 
exam and photographically documented and placed in the patient’s electronic 
chart. Tumor measurements and photography will be performed every 4 weeks 
while on study. 
 
8.2 
For visceral or other subcutaneous or soft tissue metastases, radiologic 
evaluations in the form of CT scans will be performed every 8 weeks while the 
patient remains on the study. Percentage decrease in the size of individual tumor 
lesions will be monitored and compared for different time points during the study. 

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8.3 
Tumor response to therapy for this study will be assessed using immune-related 
response criteria (irRC) which is a modified version of the WHO criteria 30. 
 
8.4 
Definition of Measureable and Non-Measurable Lesions Measurable Lesions are 
lesions that can be accurately measured in two perpendicular diameters, with at 
least one diameter > 5 mm. The area will be defined as the product of the largest 
diameter with its perpendicular. Injectable lesions will be at least 10mm in 
diameter. 
 
Non-Measurable (evaluable) Lesions are all other lesions, including 
unidimensionally measurable disease and small lesions. 
 
8.5 
Definition of Index/Non-Index Lesions 
In many patients, all measurable disease will be cutaneous, so we will allow all 
10 index lesions to be in a single organ. All measurable lesions, up to a  
maximum of ten lesions in total, should be identified as index lesions to be 
measured and recorded on the medical record at baseline. The index lesions 
should be representative of all involved organs.  In addition, index lesions should 
be selected based on their size (lesions with the longest diameters), their 
suitability for accurate repeat assessment by imaging techniques, and how 
representative they are of the patient’s tumor burden. A sum of the products of 
diameters (SPD) for all index lesions will be calculated and considered the 
baseline sum of the products of diameters. Response criteria to be followed are 
listed below. The baseline sum will be used as the reference point to determine 
the objective tumor response of the index lesions at tumor assessment (TA). 
Measurable lesions, other than index and all sites of non-measurable disease will 
be identified as non-index lesions. Non-index lesions will be recorded on the 
medical record and should be evaluated at the same assessment time points as 
the index lesions. In subsequent assessments, non-index lesions will be 
recorded as “stable or decreased disease,” “absent”, or “progression.” 
 
8.6 
Definition of Tumor Response Using irRC 
The sum of the products of diameters at tumor assessment using the immune- 
related response criteria (irRC) for progressive disease incorporates the 
contribution of new measurable lesions. Each net Percentage Change in Tumor 
Burden per assessment using irRC criteria accounts for the size and growth 
kinetics of both old and new lesions as they appear. 
 
Definition of Index Lesions Response Using irRC 
 
irComplete Response (irCR): Complete disappearance of all index lesions. 
This category encompasses exactly the same subjects as “CR” by the mWHO 
criteria. 
 
irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in 
the sum of the products of the two largest perpendicular diameters of all index 

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and all new measurable lesions (i.e., Percentage Change in Tumor Burden). 
Note: the appearance of new measurable lesions is factored into the overall 
tumor burden, but does not automatically qualify as progressive disease until the 
SPD increases by >25% when compared to SPD at nadir. 
 
irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence 
of progressive disease. 
 
irProgressive Disease (irPD): At least 25% increase Percentage Change in 
Tumor Burden (i.e., taking sum of the products of all index lesions and any new 
lesions) when compared to SPD at nadir. 
 
Definition of Non-Index Lesions Response Using irRC 
irComplete Response (irCR): Complete disappearance of all non-index lesions. 
This category encompasses exactly the same subjects as “CR” by the mWHO 
criteria 
 
irPartial Response (irPR) or irStable Disease (irSD): non-index lesions are not 
considered in the definition of PR, these terms do not apply. 
 
irProgressive Disease (irPD): Increases in number or size of non-index lesions 
does not constitute progressive disease unless/until the Percentage Change in 
Tumor Burden increases by 25% (i.e., the SPD at nadir of the index lesions 
increases by the required amount). 
 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. 
However, their contribution to total tumor burden in included in the SPD which in 
turn feeds into the irRC criteria for tumor response. Therefore, new non- 
measurable lesions will not discontinue any subject from the study. 
 
8.7 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: 
 
Immune-Related Complete Response (irCR): Complete disappearance of all 
tumor lesions (index and non-index together with no new 
measurable/unmeasurable lesions) for at least 4 weeks from the date of 
documentation of complete response. 
 
Immune-Related Partial Response (irPR): The sum of the products of the two 
largest perpendicular diameters of all index lesions is measured and captured as 
the SPD baseline.  At each subsequent tumor assessment, the sum of the 
products of the two largest perpendicular diameters of all index lesions and of 
new measurable lesions are added together to provide the Immune Response 
Sum of Product Diameters (irSPD).  A decrease, relative to baseline of the irSPD 

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compared to the previous SPD baseline, of 50% or greater is considered an 
immune Partial Response (irPR). 
 
Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet 
criteria for immune complete response or immune partial response, in the 
absence of progressive disease. 
 
Immune-Related Progressive Disease (irPD): It is recommended in difficult 
cases to confirm PD by serial imaging.  Any of the following will constitute 
progressive disease: 
• 
At least 25% increase in the sum of the products of all index lesions over 
baseline SPD calculated for the index lesions. 
• 
At least a 25% increase in the sum of the products of all index lesions and 
new measurable lesions (irSPD) over the baseline SPD calculated for the 
index lesions. 

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Immune-Related Response Criteria Definitions 
 
Index 
Lesion 
Definition 
Non-Index 
Lesion 
Definition 
New 
Measurabl 
e Lesions 
New 
Unmeasurabl 
e Lesions 
Percent 
Change in 
Tumor Burden 
Overall 
irC 
Respons 
e 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
>-50% 
<50%to<+25 
% 
>+25% 
irPR 
irSD 
irPD 
Stable 
Disease 
Any 
Any 
Any 
<50%tp<+25 
% 
>+25% 
irSD 
irPD 
Progressiv 
e Disease 
Any 
Any 
Any 
>+25% 
irPD 
 
8.8 
Immune-Related Best Overall Response Using irRC (irBOR) 
irBOR is the best confirmed irRC overall response over the study as a whole, 
recorded between the date of first dose until the last tumor assessment before 
subsequent therapy (except for local palliative radiotherapy for painful bone 
lesions) for the individual subjects in the study.  For assessment of irBOR, all 
available assessments per subject are considered. 
 
If a lesion is surgically resected or treated with definitive radiosurgery, the size of 
the lesion prior to the definitive local therapy will be included in the calculated 
irBOR. 
 
Primary evidence of antineoplastic activity will be evaluated as a function of 
objective tumor response following the vaccination period. An overall objective 
assessment of all measurable and non-measurable disease will be performed as 
outlined in 8.6. Tumor assessments should be performed by physical exam, 
ultrasound, MRI or CT scan, throughout the study. The treating physicians will 
perform tumor measurement. Radiological studies must account for all lesions 
that were present at baseline and must use the same techniques as used at 
baseline. All complete and partial responses must be confirmed by a second 
assessment at least four weeks later. 
 
 
 
9. 
Criteria for Removal from the Study 
 
Patients will be taken off the study if: (a) the patient voluntarily withdraws, (b) there is 
significant noncompliance (failure to appear to more than 2 protocol specified 
procedures), or (c) there is progression of disease in those patients after treatment. 

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Any patient who develops a DLT or Grade IV toxicity due to treatment will be taken off 
protocol. 
 
10. 
Statistical Considerations and Data Analysis 
 
The primary objective of this trial is to determine the optimal biological dose (OBD) of LL37 
based upon toxicity and efficacy. The trial will be conducted based on a phase I/II 
outcome-adaptive Bayesian dose-finding procedure (EffTox) described in Thall and Cook 
31 and Thall, Cook and Estey 32.  Under the EffTox procedure, the efficacy and toxicity of 
each dose will be monitored simultaneously and will be used to determine the desirability 
of each dose (I.e. trade-off between efficacy and toxicity) based on the accumulating dose- 
outcome data. Each time a dose must be chosen, the desirability of each dose is 
determined based on the current interim data and the next cohort is given the most 
desirable dose.  Efficacy will be defined by IFN-alpha expression at the treated tumor site 
24 hours after the first injection of LL37 (positive is defined as at least  2-fold higher IFN 
than baseline levels).  Toxicity will be defined as a DLT (defined in Section 7.2) 
experienced within the first two weeks. 
 
 
 
Each successive cohort of 2 patients (N=36) will be assigned adaptively to one of four 
dose levels of LL37, with the first cohort starting at dose level 1: 250 µg (per 1 cm3 tumor). 
Dose levels 2-4 will be 500, 1000, and 2000 µg, respectively.  Simulation results 
establishing the design’s properties under each of five potential dose-outcome scenarios 
are summarized in Table 10.1 (EffTox dose-finding v4.0). The lowest acceptable 
probability of efficacy (pE) used in the simulation was 0.20 [Pr (pE > 0.20 | data) > 0.05]. 
The highest acceptable probability of toxicity (pT) used in the simulation was 0.30 [Pr (pT 
< 0.30 | data) > 0.05]. Each scenario was simulated 1000 times.  For each scenario, 
Table 10.1 includes the desirability (see technical details), the proportion of trials that each 
dose is selected, and the average number of patients treated at each dose. Of note, if 
there is no evidence of efficacy at any dose (Scenario 3), the percent of selecting no OBD 
is 80% and only 14 patients will be treated before the study will be stopped. 

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Table 10.1:Operating Characteristics of the Design 
 
Scenario 
Dose Level 
1 
2 
3 
4 
None 
(250 
(500 
(1000 
(2000 
μg/tumor) 
μg/tumor) μg/tumor) 
μg/tumor) 
1 
True pT, pE 
.02, .05 
.03, .15 
.05, .30 
.08, .75 
- 
Desirability 
-0.20 
-0.08 
0.09 
0.55 
- 
% selected 
1 
1 
26 
72 
0 
# Patients Treated 
2.9 
2.4 
9.4 
21.2 
- 
2 
True pT, pE 
.40, .20 
.50, .40 
.60, .60 
.70, .80 
- 
Desirability 
-0.82 
-0.95 
-1.14 
-1.38 
- 
% selected 
26 
7 
4 
2 
62 
# Patients Treated 
10.4 
3.5 
2.3 
0.5 
- 
3 
True pT, pE 
.02, .01 
.03, .01 
.05, .01 
.08, .01 
- 
Desirability 
-0.25 
-0.25 
-0.27 
-0.30 
- 
% selected 
2 
0 
0 
18 
80 
# Patients Treated 
2.5 
2.0 
2.5 
7.0 
- 
4 
True pT, pE 
.10, .20 
.20, .40 
.30, .60 
.40, .80 
- 
Desirability 
-0.11 
-0.10 
-0.20 
-0.39 
- 
% selected 
34 
29 
28 
4 
5 
# Patients Treated 
11.8 
10.5 
9.9 
2.0 
- 
5 
True pT, pE 
.05, .50 
.10, .65 
.15, .80 
.20, .95 
- 
Desirability 
0.33 
0.40 
0.40 
0.32 
- 
% selected 
49 
22 
25 
4 
0 
# Patients Treated 
19.6 
7.3 
7.6 
1.5 
- 
 
Data Analyses 
 
At the end of the trial, the OBD will be determined using the algorithm above.  Safety data will 
be summarized by dose level. 

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Analyses of response will be performed on patients treated at the OBD. The rates of CR, PR, 
SD, and PD will be estimated with 95% confidence intervals.  Additionally, response will be 
defined as experiencing either a complete or partial response (CR or PR), and the association 
between response and disease characteristics and T-cell responses will be assessed using 
logistic regression.  Because we are using an adaptive design, the number of patients that will 
be treated at the OBD is unknown up front, but we expect this number to be between 19 and 
27 (from the table above).  If we have 19 patients treated at the OBD, we will have 80% power 
to detect an odds ratio of 3.6 associated with a particular covariate, assuming a logistic 
regression model with a normally distributed covariate and a Type I error rate of 5%.  If we 
have 27 patients treated at the OBD, we will have 80% power to detect an odds ratio of 2.9 
under the same assumptions. If the number of patients is between 19 and 27, the detectable 
OR will fall between 2.9 and 3.6. 
 
Time to progression and overall survival will be estimated by the Kaplan-Meier method. Cox 
proportional hazards regression models will be used to assess the association between 
survival parameters and disease and demographic factors of interest. 
 
11. 
Data Entry and Protocol Management 
 
For the purposes of this study at M. D. Anderson Cancer Center, the Protocol Data 
Management System (PDMS) will be employed. All patients will be registered in CORe 
utilizing a two-turnstile registration before any study specific tests are performed. The 
EffTox procedure will be implemented using the Biostatistics Department Clinical Trial 
Conduct Website. Concomitant medications will be captured in the medical record. 
 
The principal investigator agrees to keep all information and results concerning the 
study confidential. The confidentiality obligation applies to all personnel involved with 
this clinical trial. The Investigator must ensure that each participant’s anonymity will be 
maintained in accordance with applicable laws. The principal investigator should keep a 
separate log of ID numbers, names and addresses. Documents that contain the names 
associated with these ID numbers (e.g., written consent/assent forms), should be 
maintained by the Investigator in strict confidence except to the extent necessary to 
allow auditing by regulatory authorities, auditing or monitoring by the IRB. 
 
The Principal Investigator shall obtain all such permissions and authorizations as may 
be necessary or desirable to allow the collection and use of information protected under 
federal privacy laws and state privacy laws, including permission/authorization for 
monitoring and analysis (including re-analysis in combination with results of other 
studies), for regulatory submission purposes and for applicable reporting (if any). 
 
12. 
Administrative Procedures 
 
12.1 Changes to the Protocol: 
Any change or addition to this protocol requires a written protocol amendment 
that must be approved by the IND Office and the IRB. A copy of the written 
approval of the IRB must be received  by the IND Office and the principal 

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investigator before implementation of any changes. The IRB must review and 
approve all amendments to the protocol. This study will be monitored for 
compliance by the IND office. 
 
12.2 Ethics and Good Clinical Practice: 
This study must be carried out in compliance with the protocol and Good 
Clinical Practice, as described in: 
 
12.2.1 ICH Harmonized Tripartite Guidelines for Good Clinical Practice 
1996. 
 
12.2.2 US 21 Code of Federal Regulations dealing with clinical studies 
(including parts 50 and 56 concerning informed consent and IRB 
regulations). 
 
12.2.3 Declaration of Helsinki, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research 
Involving Human Subjects, Helsinki 1964, amended Tokyo 1975, 
Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
12.2.4 The investigator agrees, when signing the protocol, to adhere to 
the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice 

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