Note: Descriptions are shown in the official language in which they were submitted.
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CANCER THERAPY USING TOLL-LIKE RECEPTOR AGONISTS
CROSS-REFERNCE TO RELATED APPLICATION(S)
[0001] This application claims the benefit of U.S. Provisional Patent
Application No.
63/169,674, which was filed on April 1, 2021 and U.S. Provisional Patent
Application No.
63/298,589, which was filed on January 11, 2022, both of which are
incorporated by reference in
their entireties.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which has been
submitted
electronically in ASCII format and is hereby incorporated by reference in its
entirety. Said
ASCII copy, created on September 16, 2020, is named A372-502 SL.txt and is 484
bytes in size.
FIELD OF THE INVENTION
[0003] The present disclosure relates generally to methods of treating
cancer and
methods of delivering toll-like receptor (TLR) agonists to solid tumors in the
liver using a
locoregional therapy through the vasculature.
BACKGROUND OF THE INVENTION
[0004] Cancer is a devastating disease that involves the unchecked growth
of cells, which
may result in the growth of solid tumors in a variety of organs such as the
skin, liver, and
pancreas. Tumors may first present in any number of organs or may be the
result of metastases or
spread from other locations.
[0005] Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma
(ICC) are
the most common primary liver tumors and are among the solid organ
malignancies in which
progression within the liver results in a rapidly progressive and often lethal
condition.
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[0006] HCC represents more than 90% of cases of primary liver tumors.
Both HCC and
ICC patients share many of the same features and challenges with respect to
treatment. For both
diseases, the 5-year survival rate is <20%.
[0007] Surgery has been the only potential curative treatment for primary
liver cancers
such as HCC and ICC; however, approximately 70% of patients are diagnosed at
advanced
stages due to an absence of specific symptoms, and even following potentially
curative resection,
tumor relapse is frequent. Given their effectiveness in other malignancies,
checkpoint inhibitors
(CPI) have also been tried in patients with HCC and ICC; however, their
success to date has been
limited due to drug delivery challenges and suppression of immune responses in
the liver.
[0008] Accordingly, there remains a need for a safe and effective therapy
for the
treatment of primary liver cancers such as HCC and ICC.
SUMMARY OF THE INVENTION
[0009] The present invention relates to methods of treating primary liver
cancers using a
therapeutically effective amount of a toll-like receptor (TLR) agonist.
[0010] In one aspect, the present invention relates to a method of
treating primary liver
cancers comprising administering a TLR agonist through a device by hepatic
arterial infusion
(HAT). According to another embodiment, the treatment of primary liver cancers
comprises
administering a TLR agonist through a device by portal vein infusion (PVT).
[0011] In some embodiments, the TLR agonist is administered through
pressure-enabled
drug delivery (PEDD), which includes the administration of a therapeutic
through a device, such
as a catheter device. In some embodiments, the catheter device comprises a one-
way valve that
responds dynamically to local pressure changes. In some embodiments, the
catheter device
generates, causes, and/or contributes to a net increase in fluid pressure
within the vessel and/or
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target tissue or tumor. In some embodiments, the catheter device generates,
causes, and/or
contributes to a net decrease in fluid pressure within the vessel and/or
target tissue or tumor. In
some embodiments, the catheter device generates, causes, and/or contributes to
first a decrease,
then an increase in fluid pressure within the vessel and/or target tissue or
tumor.
[0012] In some embodiments, the TLR agonist is administered through a
pressure-
enabled device, such as one that modulates vascular pressure.
[0013] In some embodiments, the amount of TLR agonist administered is in
the range of
about 0.01-20 mg, or at least one of 0.5 mg, 2 mg, 4 mg, or 8 mg.
[0014] In some embodiments, the TLR agonist is administered in a solution
in the range
of 1-100 mL, or at least one of 10 mL, 25 mL, or 50 mL.
[0015] In some embodiments, the TLR agonist is administered in the range
of .0001-20
mg/mL, or at least one of .01 mg/mL, .04 mg/mL, .08 mg/mL, or .16 mg/mL.
[0016] In some embodiments, the TLR agonist is administered for a period
of time of
about 10-200 minutes. In another embodiment, the TLR agonist is administered
for a period of
time of about 10-60 minutes. In another embodiment, the TLR agonist is
administered for a
period of time of about 25 minutes.
[0017] In some embodiments, the TLR agonist is administered in
combination with one
or more CPIs. In some embodiments, the CPIs are administered systemically,
either
concurrently, before, or after the administration of the TLR agonist. In some
embodiments, the
CPIs include at least one of nivolumab, pembrolizumab, and ipilimumab.
[0018] In some embodiments, administration of the TLR agonist comprises a
dosing
regimen comprising cycles. In some embodiments, one or more of the cycles
comprise the
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administration of the TLR agonist via a catheter device by HAT followed by the
systemic
administration of one or more CPIs.
[0019] In some embodiments, one cycle of the dosing regimen comprises the
administration of the TLR agonist once per week over three consecutive weeks.
In some
embodiments, the dosing regimen comprises two cycles.
[0020] In some embodiments, the administration of a TLR agonist through
an
intravascular device to the liver results in a reduction of myeloid-derived
suppressor cells
(MDSC) or the functional alteration of MDSCs to limit immunosuppression. In
some
embodiments, the administration of a TLR agonist through an intravascular
device to the liver
results in antitumor effects.
[0021] In some embodiments, the TLR agonist is a TLR9 agonist. In some
embodiments,
the TLR9 agonist is SD-101.
[0022] These and other objects, features, and advantages of the exemplary
embodiments
of the present disclosure will become apparent upon reading the following
detailed description of
the exemplary embodiments of the present disclosure, when taken in conjunction
with the entire
specification.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Further objects, features and advantages of the present disclosure
will become
apparent from the following detailed description taken in conjunction with the
accompanying
Figures showing illustrative embodiments of the present disclosure.
[0024] FIG. 1 illustrates the structure of SD-101.
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[0025] FIG. 2 illustrates an in vitro analysis of human PMBC harvested
from healthy
donors and treated with IL6 and GM-CSF to induce MDSC.
[0026] FIG. 3 illustrates an in vitro analysis of murine bone marrow
cells, in which GM-
CSF was used to induce MD SC, from mice with or without tumor.
[0027] FIG. 4 illustrates cross-section images of swine liver lobes after
the infusion of
SD-101.
[0028] FIG. 5 illustrates the overall study design of a phase lb/2
pressure enabled
regional immune-oncology study of HAI of SD-101 with systemic checkpoint
blockade for HCC
and ICC.
[0029] Throughout the drawings, the same reference numerals and
characters, unless
otherwise stated, are used to denote like features, elements, components or
portions of the
illustrated embodiments. Moreover, while the present disclosure will now be
described in detail
with reference to the figures, it is done so in connection with the
illustrative embodiments and is
not limited by the particular embodiments illustrated in the figures and the
appended paragraphs.
DETAILED DESCRIPTION
[0030] The following description of embodiments provides non-limiting
representative
examples referencing numerals to particularly describe features and teachings
of different
aspects of the invention. The embodiments described should be recognized as
capable of
implementation separately, or in combination, with other embodiments from the
description of
the embodiments. A person of ordinary skill in the art reviewing the
description of embodiments
should be able to understand the different described aspects of the invention.
The description of
embodiments should facilitate understanding of the invention to such an extent
that other
implementations, not specifically covered but within the knowledge of a person
of skill in the art
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having read the description of embodiments, would be understood to be
consistent with
application of the invention.
Toll-like Receptor Agonists
[0031] Toll-like receptors are pattern recognition receptors that can
detect microbial
pathogen-associated molecular patterns (PAMPs). TLR stimulation, such as TLR9
stimulation,
can not only provide broad innate immune stimulation, but can also
specifically address the
dominant drivers of immunosuppression in the liver. TLR1-10 are expressed in
humans and
recognize a diverse variety of microbial PAMPs. In this regard, TLR9 can
respond to
unmethylated CpG-DNA, including microbial DNA. CpG refers to the motif of a
cytosine and
guanine dinucleotide 1. TLR9 is constitutively expressed in B cells,
plasmacytoid dendritic cells
(pDCs), activated neutrophils, monocytes/macrophages, T cells, and MDSCs. TLR9
is also
expressed in non-immune cells, including keratinocytes and gut, cervical, and
respiratory
epithelial cells. TLR9 can bind to its agonists within endosomes. Signaling
may be carried out
through MYD88/IkB/NficB to induce pro-inflammatory cytokine gene expression. A
parallel
signaling pathway through IRF7 induces type 1 and 2 interferons (e.g. IFN-a,
IFN-y, etc.) which
stimulate adaptive immune responses. Further, TLR9 agonists can induce
cytokine and IFN
production and functional maturation of antigen presenting dendritic cells.
[0032] According to an embodiment, a TLR9 agonist can reduce and
reprogram
MDSCs. MDSCs are key drivers of immunosuppression in the liver. MDSCs also
drive
expansion of other suppressor cell types such as T regulatory cells (Tregs),
tumor-associated
macrophages (TAMs), and cancer-associated fibroblasts (CAFs). MDSCs may
downregulate
immune cells and interfere with the effectiveness of immunotherapeutics.
Further, high MDSC
levels generally predict poor outcomes in cancer patients. In this regard,
reducing, altering, or
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eliminating MDSCs is thought to improve the ability of the host's immune
system to attack the
cancer as well as the ability of the immunotherapy to induce more beneficial
therapeutic
responses. In an embodiment, TLR9 agonists may convert MDSCs into
immunostimulatory MI
macrophages, convert immature dendritic cells to mature dendritic cells, and
expand effector T
cells to create a responsive tumor microenvironment to promote anti-tumor
activity.
[0033] According to an embodiment, synthetic CpG-oligonucleotides (CPG-
ONs)
mimicking the immunostimulatory nature of microbial CpG-DNA can be developed
for
therapeutic use. According to an embodiment, the oligonucleotide is an
oligodeoxynucleotide
(ODN). There are a number of different CpG-ODN class types, e.g. Class A,
Class B, Class C,
Class P, and Class S, which share certain structural and functional features.
In this regard, Class
A type CPG-ODNs (or CPG-A ODNs) are associated with pDC maturation with little
effect on B
cells as well as the highest degree of IFNa induction; Class B type CPG-ODNs
(or CPG-B
ODNs) strongly induce B-cell proliferation, activate pDC and monocyte
maturation, NK cell
activation, and inflammatory cytokine production; and Class C type CPG-ODNs
(or CPG-C
ODNs) can induce B-cell proliferation and IFN-a production.
[0034] Further, according to an embodiment, CPG-C ODNs can be associated
with the
following attributes: (i) unmethylated dinucleotide CpG motifs, (ii)
juxtaposed CpG motifs with
flanking nucleotides (e.g. AACGTTCGAA), (iii) a complete phosphorothioate (PS)
backbone
that links the nucleotides (as opposed to the natural phosphodiester (PO)
backbones found in
bacterial DNA), and (iv) a self-complimentary, palindromic sequence (e.g.
AACGTT). In this
regard, CPG-C ODNs may bind themselves due to their palindromic nature,
thereby producing
double-stranded duplex or hairpin structures.
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[0035] Further, according to an embodiment, the CPG-C ODNs can include
one or more
5'-TCG trinucleotides wherein the 5'-T is positioned 0, 1, 2, or 3 bases from
the 5'-end of the
oligonucleotide, and at least one palindromic sequence of at least 8 bases in
length comprising
one or more unmethylated CG dinucleotides. The one or more 5'-TCG
trinucleotide sequence
may be separated from the 5'-end of the palindromic sequence by 0, 1, or 2
bases or the
palindromic sequence may contain all or part of the one or more 5'-TCG
trinucleotide sequence.
In an embodiment, the CpG-C ODNs are 12 to 100 bases in length, preferably 12
to 50 bases in
length, preferably 12 to 40 bases in length, or preferably 12-30 bases in
length. In an
embodiment, the CpG-C ODN is 30 bases in length. In an embodiment, the ODN is
at least
(lower limit) 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 32, 34, 36,
38, 40, 50, 60, 70, 80, or 90 bases in length. In an embodiment, the ODN is at
most (upper limit)
100, 90, 80, 70, 60, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37,
36, 35, 34, 33, 32, 31, or
30 bases in length.
[0036] In an embodiment, the at least one palindromic sequence is 8 to 97
bases in
length, preferably 8 to 50 bases in length, or preferably 8 to 32 bases in
length. In an
embodiment, the at least one palindromic sequence is at least (lower limit) 8,
10, 12, 14, 16, 18,
20, 22, 24, 26, 28, or 30 bases in length. In an embodiment, the at least one
palindromic
sequence is at most (upper limit) 50, 48, 46, 44, 42, 40, 38, 36, 34, 32, 30,
28, 26, 24, 22, 20, 18,
16, 14, 12 or 10 bases in length.
[0037] In an embodiment, the CpG-C ODN can comprise the sequence of SEQ
ID NO:
1.
[0038] According to an embodiment, the CpG-C ODN can comprise the SD-101.
SD-
101 is a 30-mer phosphorothioate oligodeoxynucleotide, having the following
sequence:
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5'-TCG AAC GTT CGA ACG TTC GAA CGT TCG AAT-3' (SEQ ID NO: 1)
[0039] SD-101 drug substance is isolated as the sodium salt. The
structure of SD-101 is
illustrated in FIG. 1.
[0040] The molecular formula of SD-101 free acid is C293 H369 N112 0149
P29 S29 and the
molecular mass of the SD-101 free acid is 9672 Daltons. The molecular formula
of SD-101
sodium salt is C293 H340 N112 0149 P29 S29 Na29 and the molecular mass of the
SD-101 sodium salt
is 10,309 Daltons.
[0041] Further, according to an embodiment, the CPG-C ODN sequence can
correspond
to SEQ ID NO: 172 as described in U.S. Patent No. 9,422,564, which is
incorporated by
reference herein in its entirety.
[0042] In an embodiment, the CpG-C ODN can comprise a sequence that has
at least
75% homology to any of the foregoing, such as SEQ ID NO:l.
[0043] According to another embodiment the CPG-C ODN sequence can
correspond to
any one of the other sequences described in U.S. Patent No. 9,422,564.
Further, the CPG-C ODN
sequence can also correspond to any of the sequences described in U.S. Patent
No. 8,372,413,
which is also incorporated by reference herein in its entirety.
[0044] According to an embodiment, any of the CPG-C ODNs discussed herein
may be
present in their pharmaceutically acceptable salt forms. Exemplary basic salts
include
ammonium salts, alkali metal salts such as sodium, lithium, and potassium
salts, alkaline earth
metal salts such as calcium and magnesium salts, zinc salts, salts with
organic bases (for
example, organic amines) such as N-Me-D-glucamine, N-[1-(2,3-
dioleoyloxy)propy1]-N,N,N-
trimethylammonium chloride, choline, tromethamine, dicyclohexylamines, t-butyl
amines, and
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salts with amino acids such as arginine, lysine and the like. In an
embodiment, the CpG-C ODNs
are in the ammonium, sodium, lithium, or potassium salt forms. In one
preferred embodiment,
the CpG-C ODNs are in the sodium salt form. The CpG-C ODN may be provided in a
pharmaceutical solution comprising a pharmaceutically acceptable excipient.
Alternatively, the
CpG-C ODN may be provided as a lyophilized solid, which is subsequently
reconstituted in
sterile water, saline or a pharmaceutically acceptable buffer before
administration.
Pharmaceutically acceptable excipients of the present disclosure include for
instance, solvents,
bulking agents, buffering agents, tonicity adjusting agents, and
preservatives. In an embodiment,
the pharmaceutical compositions may comprise an excipient that functions as
one or more of a
solvent, a bulking agent, a buffering agent, and a tonicity adjusting agent
(e.g. sodium chloride in
saline may serve as both an aqueous vehicle and a tonicity adjusting agent).
The pharmaceutical
compositions of the present disclosure are suitable for parenteral and/or
percutaneous
administration.
[0045] In an embodiment, the pharmaceutical compositions comprise an
aqueous
vehicle as a solvent. Suitable vehicles include for instance sterile water,
saline solution,
phosphate buffered saline, and Ringer's solution. In an embodiment, the
composition is isotonic.
[0046] The pharmaceutical compositions may comprise a bulking agent.
Bulking agents
are particularly useful when the pharmaceutical composition is to be
lyophilized before
administration. In an embodiment, the bulking agent is a protectant that aids
in the stabilization
and prevention of degradation of the active agents during freeze or spray
drying and/or during
storage. Suitable bulking agents are sugars (mono-, di- and polysaccharides)
such as sucrose,
lactose, trehalose, mannitol, sorbital, glucose and raffinose.
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[0047] The pharmaceutical compositions may comprise a buffering agent.
Buffering
agents control pH to inhibit degradation of the active agent during
processing, storage and
optionally reconstitution. Suitable buffers include for instance salts
comprising acetate, citrate,
phosphate or sulfate. Other suitable buffers include for instance amino acids
such as arginine,
glycine, histidine, and lysine. The buffering agent may further comprise
hydrochloric acid or
sodium hydroxide. In some embodiments, the buffering agent maintains the pH of
the
composition within a range of 4 to 9. In an embodiment, the pH is greater than
(lower limit) 4, 5,
6, 7 or 8. In some embodiments, the pH is less than (upper limit) 9, 8, 7, 6
or 5. That is, the pH is
in the range of from about 4 to 9 in which the lower limit is less than the
upper limit.
[0048] The pharmaceutical compositions may comprise a tonicity adjusting
agent.
Suitable tonicity adjusting agents include for instance dextrose, glycerol,
sodium chloride,
glycerin, and mannitol.
[0049] The pharmaceutical compositions may comprise a preservative.
Suitable
preservatives include for instance antioxidants and antimicrobial agents.
However, in an
embodiment, the pharmaceutical composition is prepared under sterile
conditions and is in a
single use container, and thus does not necessitate inclusion of a
preservative.
[0050] Table 1 describes the batch formula for SD-101 Drug Product ¨ 16
g/L:
Table 1
Clinical Lot
DVXA05
Ingredient Grade Concentration Amount per batch
Batch Size 2.224
SD-101 Drug
GMP 1.6% 16.00 g 35.584 gl
Substance*
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Clinical Lot
DVXA05
Ingredient Grade Concentration Amount per batch
Batch Size 2.224
Sodium
phosphate,
USP/NF, EP 1.02% 1.02 g 2.268 g
dibasic
anhydrous
Sodium
phosphate,
USP 0.34% 0.34 g 0.747 g
monobasic
anhydrous
Sodium
USP/NF, EP 7.31% 7.31g 16.257g
chloride
Sterile Water
USP/NF, EP QS QS
2.224 L (kg) (QS)
for Injection
'Quantity based upon measured content in solution (to exclude moisture present
in lyophilized
powder)
* SD-101 Drug Substance in Table 1 reflects the totality of all
oligonucleotide content, including
SD-101.
[0051] In some embodiments, the unit dose strength may include from about
0.1 mg/mL
to about 20 mg/mL. In one embodiment, the unit dose strength of SD-101 is 13.4
mg/mL.
[0052] In some embodiments, the amount of SD-101 administered is in the
range of
about 0.01-20 mg, or at least one of 0.5 mg, 2 mg, 4 mg, or 8 mg.
[0053] In some embodiments, SD-101 is administered in a solution in the
range of 1-100
mL, or at least one of 10 mL, 25 mL, or 50 mL.
[0054] In some embodiments, an administered dose of SD-101 is in the
range of .0001-
20 mg/mL. In some embodiments, the administered dose of SD-101 is one of .01
mg/mL, .04
mg/mL, .08 mg/mL, or .16 mg/mL.
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[0055] CpG-C ODNs may contain modifications. Suitable modifications can
include but
are not limited to, modifications of the 3'0H or 5'0H group, modifications of
the nucleotide
base, modifications of the sugar component, and modifications of the phosphate
group. Modified
bases may be included in the palindromic sequence as long as the modified
base(s) maintains the
same specificity for its natural complement through Watson-Crick base pairing
(e.g. the
palindromic portion of the CpG-C ODN remains self-complementary). Examples of
modifications of the 5'0H group can include biotin, cyanine 5.5, the cyanine
family of dyes,
Alexa Fluor 660, the Alexa Fluor family of dyes, IRDye 700, IRDye 800, IRDye
800CW, and
the IRDye family of dyes.
[0056] CpG-C ODNs may be linear, may be circular or include circular
portions and/or
a hairpin loop. CpG-C ODNs may be single stranded or double stranded. CpG-C
ODNs may be
DNA, RNA or a DNA/RNA hybrid.
[0057] CpG-C ODNs may contain naturally-occurring or modified, non-
naturally
occurring bases, and may contain modified sugar, phosphate, and/or termini.
For example, in
addition to phosphodiester linkages, phosphate modifications include, but are
not limited to,
methyl phosphonate, phosphorothioate, phosphoramidate (bridging or non-
bridging),
phosphotriester and phosphorodithioate and may be used in any combination. In
an embodiment,
CpG-C ODNs have only phosphorothioate linkages, only phosphodiester linkages,
or a
combination of phosphodiester and phosphorothioate linkages.
[0058] Sugar modifications known in the field, such as 2'-alkoxy-RNA
analogs, 2'-
amino-RNA analogs, 2'-fluoro-DNA, and 2'-alkoxy- or amino-RNA/DNA chimeras and
others
described herein, may also be made and combined with any phosphate
modification. Examples
of base modifications include but are not limited to addition of an electron-
withdrawing moiety
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to C-5 and/or C-6 of a cytosine of the CpG-C ODN (e.g. 5-bromocytosine, 5-
chlorocytosine, 5-
fluorocytosine, 5-iodocytosine) and C-5 and/or C-6 of a uracil of the CpG-C
ODN (e.g. 5-
bromouracil, 5-chlorouracil, 5-fluorouracil, 5-iodouracil). As noted above,
use of a base
modification in a palindromic sequence of a CpG-C ODN should not interfere
with the self-
complementarity of the bases involved for Watson-Crick base pairing. However,
outside of a
palindromic sequence, modified bases may be used without this restriction. For
instance, 2'-0-
methyl-uridine and 2'-0-methyl-cytidine may be used outside of the palindromic
sequence,
whereas, 5-bromo-2'-deoxycytidine may be used both inside and outside the
palindromic
sequence. Other modified nucleotides, which may be employed both inside and
outside of the
palindromic sequence include 7-deaza-8-aza-dG, 2-amino-dA, and 2-thio-dT.
[0059] Duplex (i.e. double stranded) and hairpin forms of most ODNs are
often in
dynamic equilibrium, with the hairpin form generally favored at low
oligonucleotide
concentration and higher temperatures. Covalent interstrand or intrastrand
cross-links increase
duplex or hairpin stability, respectively, towards thermal-, ionic-, pH-, and
concentration-
induced conformational changes. Chemical cross-links can be used to lock the
polynucleotide
into either the duplex or the hairpin form for physicochemical and biological
characterization.
Cross-linked ODNs that are conformationally homogeneous and are "locked" in
their most active
form (either duplex or hairpin form) could potentially be more active than
their uncross-linked
counterparts. Accordingly, some CpG-C ODNs of the present disclosure can
contain covalent
interstrand and/or intrastrand cross-links.
[0060] The techniques for making polynucleotides and modified
polynucleotides are
known in the art. Naturally occurring DNA or RNA, containing phosphodiester
linkages, may be
generally synthesized by sequentially coupling the appropriate nucleoside
phosphoramidite to the
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5'-hydroxy group of the growing ODN attached to a solid support at the 3'-end,
followed by
oxidation of the intermediate phosphite triester to a phosphate triester.
Using this method, once
the desired polynucleotide sequence has been synthesized, the polynucleotide
is removed from
the support, the phosphate triester groups are deprotected to phosphate
diesters and the
nucleoside bases are deprotected using aqueous ammonia or other bases.
[0061] The CpG-C ODN may contain phosphate-modified oligonucleotides,
some of
which are known to stabilize the ODN. Accordingly, some embodiments include
stabilized CpG-
C ODNs. The phosphorous derivative (or modified phosphate group), which can be
attached to
the sugar or sugar analog moiety in the ODN, can be a monophosphate,
diphosphate,
triphosphate, alkylphosphonate, phosphorothioate, phosphorodithioate,
phosphoramidate or the
like.
[0062] CpG-C ODNs can comprise one or more ribonucleotides (containing
ribose as
the only or principal sugar component), deoxyribonucleotides (containing
deoxyribose as the
principal sugar component), modified sugars or sugar analogs. Thus, in
addition to ribose and
deoxyribose, the sugar moiety can be pentose, deoxypentose, hexose,
deoxyhexose, glucose,
arabinose, xylose, lyxose, and a sugar analog cyclopentyl group. The sugar can
be in pyranosyl
or in a furanosyl form. In the CpG-C oligonucleotide, the sugar moiety is
preferably the
furanoside of ribose, deoxyribose, arabinose or 2'-0-alkylribose, and the
sugar can be attached to
the respective heterocyclic bases in either anomeric configuration. The
preparation of these
sugars or sugar analogs and the respective nucleosides wherein such sugars or
analogs are
attached to a heterocyclic base (nucleic acid base) per se is known, and
therefore need not be
described here. Sugar modifications may also be made and combined with any
phosphate
modification in the preparation of a CpG-C ODN.
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[0063] The heterocyclic bases, or nucleic acid bases, which are
incorporated in the CpG-
C ODN can be the naturally-occurring principal purine and pyrimidine bases,
(namely uracil,
thymine, cytosine, adenine and guanine, as mentioned above), as well as
naturally-occurring and
synthetic modifications of said principal bases. Thus, a CpG-C ODN may include
one or more of
inosine, 2'-deoxyuridine, and 2-amino-2'-deoxyadenosine.
[0064] According to another embodiment, the CPG-ODN is one of a Class A
type CPG-
ODNs (CPG-A ODNs), a Class B type CPG-ODNs (CPG-B ODNs), a Class P type CPG-
ODNs
(CPG-P ODN), and a Class S type CPG-ODNs (CPG-S ODN). In this regard, the CPG-
A ODN
can be CMP-001.
[0065] In another embodiment, the CPG-ODN can be tilsotolimod (IMO-2125).
[0066] Further, according to an embodiment, in vitro studies of human
peripheral blood
mononuclear cells (PMBC) demonstrate that SD-101 is superior to Class B TLR9
agonist and a
TLR7 agonist with respect to reduction of MDSC, reduction of M2 macrophages,
and promotion
of M1 macrophages. For example, FIG. 2 depicts an in vitro analysis of human
PMBC harvested
from healthy donors and treated with IL6 and GM-CSF to induce MDSC. In this
regard, SD-101
demonstrated (i) better elimination of the dominant MDSC subset in the liver,
e.g., M-MDSC
and (ii) a more favorable effect on the M1/M2 macrophage ratio (i.e.,
induction of M1 and
reduction of M2).
[0067] Further, according to an embodiment, in vitro studies of murine
bone marrow
cells demonstrate that SD-101 is similarly superior to a Class B TLR9 agonist
and a TLR7
agonist for murine myeloid cell programming. For example, FIG. 3 depicts an in
vitro analysis of
murine bone marrow cells, in which GM-CSF was used to induce MDSC, from mice
with or
without tumor. In this regard, SD-101 was superior to class A TLR9, class B
TLR9, and TLR7
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agonists in reduction of MDSC and M2 macrophages, in addition to induction of
M1
macrophages.
Checkpoint Inhibitors
[0068] According to an embodiment, the TLR agonists of the present
invention may be
used in combination with one or more CPIs. The CPI can include a Programmed
Death 1
receptor (PD-1) antagonist. A PD-1 antagonist can be any chemical compound or
biological
molecule that blocks binding of Programmed Cell Death 1 Ligand 1 (PD-L1)
expressed on a
cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell)
and preferably also
blocks binding of PD-L2 Programmed Cell Death 1 Ligand 2 (PD-L2) expressed on
a cancer cell
to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and
its ligands
include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4,
CD274
and B7-H for PD-Li; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any
of the
treatment methods, medicaments and uses of the present invention in which a
human individual
is being treated, the PD-1 antagonist blocks binding of human PD-Li to human
PD-1, and
preferably blocks binding of both human PD-Li and PD-L2 to human PD-1.
[0069] According to an embodiment, the PD-1 antagonist can include a
monoclonal
antibody (mAb), or antigen binding fragment thereof, which specifically binds
to PD-1 or PD-
L1, and preferably specifically binds to human PD-1 or human PD-Li. The mAb
may be a
human antibody, a humanized antibody or a chimeric antibody, and may include a
human
constant region. In some embodiments the human constant region is selected
from the group
consisting of IgGl, IgG2, IgG3 and IgG4 constant regions, and in preferred
embodiments, the
human constant region is an IgG1 or IgG4 constant region. In some embodiments,
the antigen
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binding fragment is selected from the group consisting of Fab, Fab'-SH,
F(a1302, scFv and Fv
fragments.
[0070] According to an embodiment, the PD-1 antagonist can include an
immunoadhesin that specifically binds to PD-1 or PD-L1, and preferably
specifically binds to
human PD-1 or human PD-L1, e.g. a fusion protein containing the extracellular
or PD-1 binding
portion of PD-Li or PD-L2 fused to a constant region such as an Fc region of
an
immunoglobulin molecule.
[0071] According to an embodiment, the PD-1 antagonist can block PD-Li
expressed
by tumor cells and MDSC, and other suppressive immune cells.
[0072] According to an embodiment, the PD-1 antagonist can inhibit the
binding of PD-
Li to PD-1, and preferably also inhibits the binding of PD-L2 to PD-1. In some
embodiments of
the above treatment method, medicaments and uses, the PD-1 antagonist is a
monoclonal
antibody, or an antigen binding fragment thereof, which specifically binds to
PD-1 or to PD-Li
and blocks the binding of PD-Li to PD-1. In one embodiment, the PD-1
antagonist is an anti-
PD-1 antibody which comprises a heavy chain and a light chain.
[0073] According to an embodiment, the PD-1 antagonist can be one of
nivolumab,
pembrolizumab, cemiplimab, and dostarlimab.
[0074] According to an embodiment, nivolumab is administered
intravenously (IV) via
a peripheral vein at a dose of 480 mg every four weeks ("Q4W") or 240 mg every
two weeks
("Q2W"). According to another embodiment, nivolumab is administered
intravenously (IV) via
a peripheral vein at a dose of nivolumab 360 mg every three weeks ("Q3W"). In
another
embodiment, nivolumab dosing is weight-based, at nivolumab 3 mg/kg Q2W or 10
mg/kg Q2W.
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In another embodiment, nivolumab dosing is weight-based at nivolumab 1 mg/kg
Q3W. In yet
another embodiment, nivolumab is administered concomitantly, at the same time,
at about the
same time, or on the same day with SD-101. In another embodiment, nivolumab is
administered
one a weekly, every other week, every three weeks, every four weeks, or on a
monthly basis
following the administration of one or more cycles of SD-101.
[0075] According to another embodiment, pembrolizumab is administered
intravenously
(IV) via a peripheral vein at a dose of 200 mg Q3W or 400 mg every 6 weeks
("Q6W"). In
another embodiment, pembrolizumab is administered concomitantly, at the same
time, at about
the same time, or on the same day with SD-101.
[0076] According to another embodiment, the CPI can include a PD-Li
antagonist. In
this regard, the PD-Li antagonist can be one of atezolizumab, avelumab, and
durvalumab.
[0077] According to another embodiment, the CPI can include a CTLA-4
antagonist. In
this regard, the CTLA-4 antagonist can be ipilimumab.
[0078] According to an embodiment, ipilimumab is administered
intravenously (IV) via
a peripheral vein at a dose of 3 mg/kg every three weeks. In yet another
embodiment,
ipilimumab is administered concomitantly, at the same time, at about the same
time, or on the
same day with SD-101 and/or nivolumab. In another embodiment, ipilimumab is
administered
once a week, every other week, every three weeks, every four weeks, or on a
monthly basis
following the administration of one or more cycles of SD-101 and/or nivolumab.
Devices to Achieve Locoregional Delivery
[0079] According to an embodiment, any of the above-described devices may
comprise
any device useful to achieve locoregional delivery to a tumor, including a
catheter itself, or may
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comprise a catheter along with other components (e.g. filter valve, balloon,
pressure sensor
system, pump system, syringe, outer delivery catheter, etc.) that may be used
in combination
with the catheter. In certain embodiments, the catheter is a microcatheter.
[0080] In some embodiments, the device may have one or more attributes
that include,
but are not limited to, self-centering capability that can provide homogeneous
distribution of
therapy in downstream branching network of vessels; anti-reflux capability
that can block or
inhibit the retrograde flow of the TLR agonist (for example, with the use of a
valve and filter,
and/or balloon); a system to measure the pressure inside the vessel; and a
means to modulate the
pressure inside the vessel, such as by causing a decrease in pressure at
placement and during the
TLR agonist infusion, and an increase of pressure during saline bolus or
during bolus infusion of
the TLR agonist. In some embodiments, the system is designed to continuously
monitor real-
time pressure or flow throughout the procedure.
[0081] In some embodiments, the device that may be used to perform the
methods of the
present invention is a device as disclosed in U.S. Patent No. 8,500,775, U.S.
Patent No.
8,696,698, U.S. Patent No. 8,696,699, U.S. Patent No. 9,539,081, U.S. Patent
No. 9,808,332,
U.S. Patent No. 9,770,319, U.S. Patent No. 9,968,740, U.S. Patent No.
10,813,739, U.S. Patent
No. 10,588,636, U.S. Patent No. 11,090,460, U.S. Patent Publication No.
2018/0193591, U.S.
Patent Publication No. 2018/0250469, U.S. Patent Publication No. 2019/0298983,
U.S. Patent
Publication No. 2020/0038586, and U.S. Patent Publication No. 2020-0383688,
which are all
incorporated by reference herein in their entireties.
[0082] In some embodiments, the device is a device as disclosed in U.S.
Patent No.
9,770,319. In certain embodiments, the device may be a device known as the
Surefire Infusion
System.
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[0083] In some embodiments, the device supports the measurement of
intravascular
pressure during use. In some embodiments, the device is a device as disclosed
in U.S. Patent
Publication No. 2020-0383688. In certain embodiments, the device may be a
device known as
the TriSalus Infusion System. In certain embodiments, the device may be a
device known as the
TriNav Infusion System. The TriNav is a single lumen catheter equipped with
a one-way
valve that responds dynamically to local pressure and flow changes, such as
those arising from
the cardiac cycle or generated by infusion. The valve structure modulates
distal vascular
pressures and blood flow. This in turn may alter therapeutic distribution and
first-pass
absorption due to increased contact time within the vasculature.
[0084] In some embodiments, the TLR agonist may be administered through a
device
via PEDD. In some embodiments, the TLR agonist may be administered while
monitoring the
pressure in the vessel, which can be used to adjust and correct the
positioning of the device at the
infusion site and/or to adjust the rate of infusion. Pressure may be monitored
by, for example, a
pressure sensor system comprising one or more pressure sensors.
[0085] The rate of infusion may be adjusted to alter vascular pressure or
flow, which may
promote the penetration and/or binding of the TLR agonist into the target
tissue or tumor or at its
surface. In some embodiments, the rate of infusion may be adjusted and/or
controlled using a
syringe pump as part of the delivery system or by any other method (e.g., an
infusion flow rate
regulating device). In some embodiments, the rate of infusion may be adjusted
and/or controlled
using a pump system. In some embodiments, the rate of infusion using a pump
system may be
about 0.1 cc/min to about 40 cc/min, or about 0.1 cc/min to about 30 cc/min,
or about 0.5 cc/min
to about 25 cc/min, or about 0.5 cc/min to about 20 cc/min, or about 1 cc/min
to about 15 cc/min,
or about 1 cc/min to about 10 cc/min, or about 1 cc/min to about 8 cc/min, or
about 1 cc/min to
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about 5 cc/min. Further, the rate of infusion using a bolus infusion may be
about 30 cc/min to
about 360 cc/min, or about 120 cc/min to about 240 cc/min. In one embodiment
the SD-101
infusion procedure lasts approximately 10-200 minutes. In another embodiment
the SD-101
infusion procedure lasts approximately 10-60 minutes. In another embodiment
the SD-101
infusion procedure lasts approximately 25 minutes.
Methods Comprising Administration to the Liver
[0086] In an embodiment, the methods of the present invention include
methods of
treating a solid tumor in the liver, such as a tumor that is the result of at
least one primary liver
cancer such as HCC and ICC or a tumor having features of both HCC and ICC,
said method
comprising administering a toll-like receptor agonist to a patient in need
thereof, wherein the
toll-like receptor agonist is administered through a device by HAI to such
solid tumor in the
liver. HAI refers to the infusion of a treatment into the hepatic artery of
the liver or branches of
the hepatic artery. According to an embodiment, the toll-like receptor agonist
or agonists are
introduced through the percutaneous introduction of a device into the branches
of a hepatic artery
or portal vein, such as a catheter and/or a device that facilitates pressure-
enabled delivery.
According to an embodiment, the toll-like receptor agonist is a TLR9 agonist
and in some
embodiments the TLR9 agonist is SD-101. In one embodiment, the patient is a
human patient.
According to another embodiment, the methods include administration to a
subject who is male
or female, and is eighteen years of age or older.
[0087] According to another embodiment, the methods of the present
invention include
methods of treating a solid tumor in the liver, such as a tumor that is the
result of at least one
primary liver cancer such as HCC and ICC or a tumor having features of both
HCC and ICC,
said method comprising administering a toll-like receptor agonist to a patient
in need thereof,
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wherein the toll-like receptor agonist is administered through a device by PVI
to such solid
tumor in the liver. PVI refers to the infusion of a treatment into the hepatic
portal venous system.
According to an embodiment, the toll-like receptor agonist or agonists are
introduced through the
percutaneous introduction of a device into the branches of the hepatic portal
venous system, such
as a catheter and/or a device that facilitates pressure-enabled delivery.
According to an
embodiment, the toll-like receptor agonist is a TLR9 agonist and in some
embodiments the
TLR9 agonist is SD-101. In one embodiment, the patient is a human patient.
[0088] According to another embodiment, the methods of the present
invention include
a method for treating at least one primary liver cancer such as HCC and ICC or
a tumor having
features of both HCC and ICC, wherein the subject has not received prior
cytotoxic
chemotherapy, targeted therapy, or external radiation therapy within 14 days
prior to enrollment.
According to yet another embodiment, methods of the present invention are
administered to
subject who have not ever received therapy with SD-101. According to an
embodiment of the
invention, methods also include administration to subject who have not ever
received prior
embolic HAI therapy with permanent embolic material.
[0089] According to another embodiment, methods of the present invention
include a
method for treating at least one primary liver cancer such as HCC and ICC or a
tumor having
features of both HCC and ICC, wherein the subject has no prior history of or
other concurrent
malignancy unless the malignancy is clinically insignificant. In another
embodiment, subjects
who are treated according to the methods of the present invention may have no
ongoing
treatment. In yet another embodiment, the subject is clinically stable.
[0090] In another embodiment, methods of the present invention may
include
administration to a subject who has measurable disease in the liver according
to RECIST v.1.1
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criteria. In an additional embodiment, methods of the present invention may
include
administration to a subject who exhibits an Eastern Cooperative Oncology Group
(ECOG)
performance score (PS) of 0-1 at screening. In another embodiment, subjects
who are
administered therapy according to methods of the present invention have a life
expectancy of
greater than 3 months at screening as estimated by the investigator. In yet
another embodiment,
subjects have a QTc interval <480 msec.
[0091] In another embodiment, all associated clinically significant drug-
related toxicity
from previous cancer therapy is resolved prior to treatment. In this
embodiment, resolution is to
Grade <1 or the patient's pretreatment level. In an additional embodiment, the
subject may have
Grade 2 alopecia and endocrinopathies controlled on replacement therapy.
[0092] In another embodiment, methods of the present invention may
include
administration to a subject who has adequate organ function at screening. In
an embodiment, a
subject with adequate organ function may exhibit one or more of the following:
(i) platelet count
>100,000/[tL, (2) hemoglobin >8.0 g/dL, (3) white blood cell count (WBC)
>2,000/[iL (4) Serum
creatinine <2.0 mg/dL unless the measured creatinine clearance is >30 mL/min
calculated by
Cockcroft-Gault formula, (5) total and direct bilirubin <2.0 x the upper limit
of normal (ULN)
and alkaline phosphatase <5 x ULN, (6) for patients with documented Gilbert's
disease, total
bilirubin up to 3.0 mg/dL, (7) ALT and AST <5 x ULN, and (8) prothrombin
time/International
Normalized Ratio (INR) or activated partial thromboplastin time (aPTT) test
results at screening
<1.5 x ULN (this applies only to patients who do not receive therapeutic
anticoagulation;
patients receiving therapeutic anticoagulation should be on a stable dose for
at least 4 weeks
prior to the first dose of study intervention).
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[0093] According to one or more embodiments, the methods of the present
invention
include methods for treating a primary liver cancer, such as HCC or ICC,
wherein the subject has
histologically or cytologically confirmed HCC or ICC with liver-only or liver-
dominant disease.
Liver-dominant disease may present with intrahepatic disease representing the
largest fraction of
disease, or if progression of HCC or ICC represents a significant threat to
the patient's life.
[0094] In one or more embodiments, methods of the present invention may
include
administration to a subject who has a designation of class A on the Child¨Pugh
liver function
scale (a three-category scale [A, B, or C], with C indicating the most severe
compromise of liver
function). In one or more additional embodiments, methods of the present
invention may include
administration to a subject with adequate hematologic and organ function.
[0095] In one or more embodiments, methods of the present invention may
include
administration to a subject who previously received at least 1 standard line
of systemic therapy
for liver cancer and with persistent or progressive measurable disease, as
defined by RECIST
version 1.1, that is not amenable to curative therapies.
[0096] According to another embodiment, the tumor is unresectable.
[0097] According to another embodiment, the methods of the present
invention can be
administered with other cancer therapeutics such as immuno-modulators, tumor-
killing agents,
and/or other targeted therapeutics.
[0098] According to an embodiment, TLR9 therapy may be administered in
combination with cell therapy (thereby enabling cell therapy by modulation of
the immune
system), chemoembolic treatment, or radioembolic treatment.
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[0099] In one embodiment, the above methods of administration to the
liver are
intended to result in the penetration of the toll-like receptor agonist
throughout the solid tumor,
throughout the entire organ, or substantially throughout the entire tumor. In
an embodiment, such
methods enhance perfusion of the toll-like receptor agonist to a patient in
need thereof, including
by overcoming interstitial fluid pressure and solid stress of the tumor. In
another embodiment,
perfusion throughout an entire organ or portion thereof, may provide benefits
for the treatment of
the disease by thoroughly exposing the tumor to therapeutic agent. In an
embodiment, such
methods are better able to afford delivery of the toll-like receptor to areas
of the tumor that have
poor access to systemic circulation. In another embodiment, such methods
deliver higher
concentrations of the toll-like receptor agonist into such a tumor with less
toll-like receptor
agonist delivered to nontarget tissues compared to conventional systemic
delivery via a
peripheral vein. Nontarget tissues are tissues directly perfused by the
arterial network in
immediate connection with the infusion device. In one embodiment, such methods
result in the
reduction in size, reduction in growth rate, or shrinkage or elimination of
the solid tumor.
[00100] The methods of the present invention may also include mapping the
vessels
leading to the right and left lobes of the liver prior to performing HAI, or
selective infusion into
specific sectors or segments, and when necessary, occluding vessels that do
not lead to the liver
or that are otherwise not a target. In some embodiments, prior to infusion,
patients can undergo a
mapping angiogram, e.g. via a common femoral artery approach.
[00101] Methods for mapping vessels in the body and delivery of
therapeutics are well
known to the ordinarily skilled artisan. Occlusion may be achieved, for
example, through the use
of microcoil embolization, which allows the practitioner to block off-target
arteries or vessels,
thereby optimizing delivery of the modified cells to the liver. Microcoil
embolization can be
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performed as needed, such as prior to administering the first dose of TLR9
agonists to facilitate
optimal infusion of a pharmaceutical composition comprising the TLR9 agonists.
In another
embodiment, a sterile sponge (e.g. GELFOAM) can be used. In this regard, the
sterile sponge
can be cut and pushed into the catheter. In another embodiment, the sterile
sponge can be
provided as granules.
[00102] In
some embodiments, doses of a TLR9 agonist, such as SD-101 may be about
0.01 mg, about 0.03 mg, about 0.05 mg, about 0.1 mg, about 0.3 mg, about 0.5
mg, about 1 mg,
about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg,
about 4.5 mg,
about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg,
or about 8 mg.
In some embodiments, SD-101 is administered at doses of 12 mg, 16 mg, and 20
mg.
Administration of a milligram amount of SD-101 (e.g. about 2 mg) describes
administering
about 2 mg of the composition illustrated in FIG. 1. For example, such an
amount of SD-101
(e.g. about a 2 mg amount) may also exist within a composition that contains
material in addition
to such amount of SD-101, such as other related and unrelated compounds.
Equivalent molar
amounts of other pharmaceutically acceptable salts are also contemplated.
[00103] In some embodiments, doses of a TLR9 agonist, such as SD-101, may
be
between about 0.01 mg and about 20 mg, about 0.01 mg and about 10 mg, between
about 0.01
mg and about 8 mg, and between about 0.01 mg and about 4 mg. In some
embodiments, doses
of a TLR9 agonist, such as SD-101 may be between about 2 mg and about 10 mg,
between about
2 mg and about 8 mg, and between about 2 mg and about 4 mg. In some
embodiments, doses of
a TLR9 agonist, such as SD-101 may be less than about 10 mg, less than about 8
mg, less than
about 4 mg, or less than about 2 mg. Such doses may be administered daily,
weekly, or every
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other week. In one embodiment, doses of SD-101 are incrementally increased,
such as through
administration of about 2 mg, followed by about 4 mg, and then followed by
about 8 mg.
[00104] In some embodiments, the methods of the present invention may
comprise
administering a dosing regimen comprising cycles, in which one or more of the
cycles comprise
administering SD-101 via HAT and PEDD. As used herein, a "cycle" is a repeat
of a dosing
sequence. In one embodiment, one cycle comprises three weekly doses per cycle
(i.e.
administration of SD-101 once per week over three consecutive weeks). In one
embodiment, a
cycle of treatment according to the present invention may comprise periods of
SD-101
administration followed by "off' periods or rest periods. In another
embodiment, in addition to
three weekly doses per cycle, the cycle further comprises one week, two weeks,
three weeks, or
four weeks as a rest period following the weekly administration of SD-101. In
yet another
embodiment, in addition to three weekly doses per cycle, the cycle further
comprises about
thirty-eight days as a rest period following the weekly administration of SD-
101. In another
embodiment, the entire cycle comprises about fifty-two days. In another
embodiment, the dosing
regimen comprises at least one, at least two, or at least three cycles, or
longer.
[00105] In some embodiments, the present invention relates to the use of a
TLR9 agonist
in the manufacture of a medicament for treating a solid tumor in the liver,
such as a tumor that is
the result of a primary liver cancer such as HCC and ICC, said method
comprising administering
the TLR9 agonist to a patient in need thereof, wherein the TLR9 agonist is
administered through
a device by HAT to such solid tumor in the liver.
[00106] In some embodiments, SD-101 is administered for the treatment of
primary liver
cancers such as HCC and ICC at a dose of 0.5 mg through HAT, and in some
embodiments, the
SD-101 is further administered through a device that modulates pressure (i.e.
PEDD). In some
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embodiments, SD-101 is administered at a dose of 0.5 mg through HAT through a
device that
modulates vascular pressure in combination with a CPI, wherein the CPI is
nivolumab. In other
embodiments, SD-101 is administered at a dose of 0.5 mg through HAT and
through a device that
modulates pressure in combination with ipilimumab. In some embodiments, SD-101
is
administered at a dose of 0.5 mg through HAT and through a device that
modulates pressure in
combination with ipilimumab and nivolumab. In other embodiments, SD-101 is
administered at
a dose of 0.5 mg through HAT and through a device that modulates pressure in
combination with
pembrolizumab.
[00107] In some embodiments, SD-101 is administered for the treatment of
primary liver
cancers such as HCC and ICC at a dose of 2 mg through HAT, and in some
embodiments, the
SD-101 is further administered through a device that modulates pressure (i.e.
PEDD). In some
embodiments, SD-101 is administered at a dose of 2 mg through HAT through a
device that
modulates vascular pressure in combination with a CPI, wherein the CPI is
nivolumab. In other
embodiments, SD-101 is administered at a dose of 2 mg through HAT and through
a device that
modulates pressure in combination with ipilimumab. In some embodiments, SD-101
is
administered at a dose of 2 mg through HAT and through a device that modulates
pressure in
combination with ipilimumab and nivolumab. In other embodiments, SD-101 is
administered at
a dose of 2 mg through HAT and through a device that modulates pressure in
combination with
pembrolizumab.
[00108] In some embodiments, SD-101 is administered for the treatment of a
primary
liver cancer such as HCC and ICC at a dose of 4 mg through HAT, and in some
embodiments, the
SD-101 is further administered through a device that modulates pressure (i.e.
PEDD). In some
embodiments, SD-101 is administered at a dose of 4 mg through HAT through a
device that
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modulates vascular pressure in combination with a CPI, wherein the CPI is
nivolumab. In other
embodiments, SD-101 is administered at a dose of 4 mg through HAT and through
a device that
modulates pressure in combination with ipilimumab. In some embodiments, SD-101
is
administered at a dose of 4 mg through HAT and through a device that modulates
pressure in
combination with ipilimumab and nivolumab. In other embodiments, SD-101 is
administered at
a dose of 4 mg through HAT and through a device that modulates pressure in
combination with
pembrolizumab.
[00109] In some embodiments, SD-101 is administered for the treatment of a
primary
liver cancer such as HCC and ICC at a dose of 8 mg through HAT, and in some
embodiments, the
SD-101 is further administered through a device that modulates pressure (i.e.
PEDD). In some
embodiments, SD-101 is administered at a dose of 8 mg through HAT through a
device that
modulates vascular pressure in combination with a CPI, wherein the CPI is
nivolumab. In other
embodiments, SD-101 is administered at a dose of 8 mg through HAT and through
a device that
modulates pressure in combination with ipilimumab. In some embodiments, SD-101
is
administered at a dose of 8 mg through HAT and through a device that modulates
pressure in
combination with ipilimumab and nivolumab. In other embodiments, SD-101 is
administered at
a dose of 8 mg through HAT and through a device that modulates pressure in
combination with
pembrolizumab.
[00110] In one or more embodiments, methods of the present invention may
include
administering up to 6 doses (maximum of 2 cycles of SD-101, 3 weekly doses per
cycle) to a
subject. In one or more embodiments, fewer doses or cycles of SD-101 may be
administered
based on toxicity or tolerability of the subject.
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[00111] In
one or more embodiments, a solution of SD-101 may be administered to a
subject via HAT using a PEDD device, such as the TriNav . In some such
embodiments, vascular
access may be achieved using the femoral artery or radial artery approach.
Hemangiomata,
shunting vessels, or other vascular lesions in the liver that may interfere
with therapeutic delivery
may be embolized at the discretion of the treating interventional radiology
specialist. In one or
more embodiments, the SD-101 can be prepared and delivered in a 50 mL syringe
(therapeutic
dose) and a 100-mL vial containing the volume necessary for the therapeutic
flush (10 mL), both
at the therapeutic concentration. The PEDD device can then be advanced into
the target vessels.
[00112] In one or more embodiments, the 50 mL solution of SD-101 can be
allocated by
per segment or sector of the liver. In one or more embodiments, the 50-mL
therapeutic dose of
SD-101 can be allocated as follows: 3 x 10 mL infusions into target blood
vessels in the right
hepatic lobe and 2 x 10 mL infusions into target blood vessels in the left
hepatic lobe. Further,
the distribution of the 10-mL aliquots may be adjusted based on the location
of measurable
disease and target vessel diameter. In one or more embodiments, the SD-101
infusion can be
expected to last approximately 10-60 minutes. For example, in some
embodiments, the infusion
time can be approximately 25 minutes. Further, in another embodiment, the
overall
interventional procedure can last between 30-80 minutes. This involves all the
handling time
between infusions in different locations. In some embodiments, the 50 mL
solution of SD-101
can include one of 0.5 mg, 2 mg, 4 mg, or 8 mg of SD-101. In this regard, the
infused dose of
SD-101 can be one of .01 mg/mL, .04 mg/mL, .08 mg/mL, or .16 mg/mL.
[00113] According to another embodiment, the SD-101 can be prepared and
delivered in a
25 mL solution. In some embodiments, the 25 mL solution of SD-101 can include
one of 0.5 mg,
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2 mg, 4 mg, or 8 mg of SD-101. In this regard, the infused dose of SD-101 can
be one of .02
mg/mL, .08 mg/mL, .16 mg/mL, or .32 mg/mL.
[00114] According to another embodiment, the SD-101 can be prepared and
delivered in a
mL solution. In some embodiments, the 10 mL solution of SD-101 can include one
of 0.5 mg,
2 mg, 4 mg, or 8 mg of SD-101. In this regard, the infused dose of SD-101 can
be one of .05
mg/mL, .2 mg/mL, .4 mg/mL, or .8 mg/mL.
[00115] In some embodiments, the methods of the present invention result
in the
treatment of target lesions. In this embodiment, the methods of the present
invention may result
in a complete response, comprising the disappearance of all target lesions. In
some
embodiments, the methods of the present invention may result in a partial
response, comprising
at least a 30% decrease in the sum of the longest diameter of target lesions,
taking as reference
the baseline sum longest diameter. In some embodiments, the methods of the
present invention
may result in stable disease of target lesions, comprising neither sufficient
shrinkage to qualify
for partial response nor sufficient increase to qualify for progressive
disease, taking as reference
the smallest sum longest diameter since the treatment started. In such an
embodiment,
progressive disease is characterized by at least a 20% increase in the sum of
the longest diameter
of target lesions, taking as reference the smallest sum longest diameter
recorded since the
treatment started or the appearance of one or more new lesions. The sum must
demonstrate an
absolute increase of 5 mm.
[00116] In another embodiment, the methods of the present invention result
in the
treatment of nontarget lesions. Nontarget lesions are lesions not directly
perfused by the arterial
network in immediate communication with the infusion system. In this
embodiment, the methods
of the present invention may result in a complete response, comprising the
disappearance of all
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nontarget lesions. In some embodiments, the methods of the present invention
result in
persistence of one or more nontarget lesion(s), while not resulting in a
complete response or
progressive disease. In such an embodiment, progressive disease is
characterized by unequivocal
progression of existing nontarget lesions, and/or the appearance of one or
more new lesions.
[00117] In some embodiments, the methods of the present invention result
in a beneficial
overall response rate, such as an overall response rate according to RECIST
v.1.1. In those
embodiments, the methods of the present invention result in an overall
response that is a
complete response wherein the subject exhibits a complete response of target
lesions, a complete
response of nontarget lesions, and no new lesions. In other embodiments, the
methods of the
present invention result in an overall response that is a partial response,
wherein the subject
exhibits a complete response for target lesions, non-complete response and non-
progressive
disease for nontarget lesions, and no new lesions. In other embodiments, the
methods of the
present invention result in an overall response that is a partial response,
wherein the subject
exhibits a partial response for target lesions, non-progressive disease for
nontarget lesions, and
no new lesions. In another embodiment, the methods of the present invention
result in an overall
response that is stable disease wherein the subject exhibits stable disease of
target lesions, non-
progressive disease for nontarget lesions, and no new lesions.
[00118] In some embodiments, the methods of the present invention result
in an
increased duration of overall response. In some embodiments, the duration of
overall response is
measured from the time measurement criteria are met for complete response or
partial response
(whichever is first recorded) until the first date that recurrent or
progressive disease is objectively
documented (taking as reference for progressive disease the smallest
measurements recorded
since the treatment started). The duration of overall complete response may be
measured from
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the time measurement criteria are first met for complete response until the
first date that
progressive disease is objectively documented. In some embodiments, the
duration of stable
disease is measured from the start of the treatment until the criteria for
progression are met,
taking as reference the smallest measurements recorded since the treatment
started, including the
baseline measurements.
[00119] In yet other embodiments, the methods of the present invention
result in
improved overall survival rates. For example, overall survival may be
calculated from the date
of enrollment to the time of death. Patients who are still alive prior to the
data cutoff for final
efficacy analysis, or who dropout prior to study end, will be censored at the
day they were last
known to be alive.
[00120] In other embodiments, the methods of the prevent invention result
in
progression-free survival. For instance, progression-free survival may be
calculated from the
date of enrollment to the time of CT scan documenting relapse (or other
unambiguous indicator
of disease development), or date of death, whichever occurs first. Patients
who have no
documented relapse and are still alive prior to the data cutoff for final
efficacy analysis, or who
drop out prior to study end, will be censored at the date of the last
radiological evidence
documenting absence of relapse.
[00121] In some embodiments, the methods of the present invention result
in a beneficial
overall response rate, such as an overall response rate according to mRECIST.
In those
embodiments, the methods of the present invention result in an overall
response that is a
complete response wherein the subject exhibits a complete response of target
lesions, a complete
response of nontarget lesions, and no new lesions. In other embodiments, the
methods of the
present invention result in an overall response that is a partial response,
wherein the subject
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exhibits a complete response for target lesions, non-complete response and
incomplete response
for nontarget lesions, and no new lesions. In other embodiments, the methods
of the present
invention result in an overall response that is a partial response, wherein
the subject exhibits a
partial response for target lesions, non-progressive disease for nontarget
lesions, and no new
lesions. In another embodiment, the methods of the present invention result in
an overall
response that is stable disease wherein the subject exhibits stable disease of
target lesions, non-
progressive disease for nontarget lesions, and no new lesions.
[00122] In some embodiments, the methods of the present invention result
in a beneficial
overall response rate, such as an overall response rate according to iRECIST.
[00123] According to another embodiment, the methods of the present
invention include
a method for treating a primary liver cancer such as HCC and ICC, wherein the
administration of
SD-101 results in a reduction of tumor burden. In some embodiments, the tumor
burden is
reduced by about 10%, by about 20%, by about 30%, by about 40%, by about 50%,
by about
60%, by about 70%, by about 80%, by about 90%, or by about 100%.
[00124] According to another embodiment, the methods of the present
invention include
a method for treating a primary liver cancer such as HCC and ICC, wherein the
administration of
SD-101 results in a reduction of tumor progression or stabilization of tumor
growth. In some
embodiments, tumor progression is reduced by about 10%, by about 20%, by about
30%, by
about 40%, by about 50%, by about 60%, by about 70%, by about 80%, by about
90%, or by
about 100%.
[00125] According to another embodiment, the methods of the present
invention include
a method for treating a primary liver cancer such as HCC and ICC, wherein the
administration of
SD-101 reprograms the liver MDSC compartment to enable immune control of the
liver cancer
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and/or improves responsiveness to systemic anti-PD-1 therapy through
elimination of MDSC. In
some embodiments, the methods of the present invention are superior in
controlling MDSC. In
some embodiments, the methods of the present invention include a method for
treating primary
liver cancers such as HCC and ICC, wherein the administration of SD-101
reduces the frequency
of MDSC cells (CD11b+Grl+), monocytic MDSC (M-MDSC; CD11b+Ly6C+) cells,
granulocytic MDSC (G-MDSC; CD11b+LY6G+) cells, or human MDSC
(CD33+CD11b+HLADR- (CD14+ for m-MDSC and CD15+ for G-MDSC)). According to
another embodiment, the methods of the present invention enhance M1
macrophages (CD14+
CD86+). According to yet another embodiment, the methods of the present
invention decrease
M2 macrophages (CD14+ CD163+CD206+).
[00126] In another embodiment, the methods of the present invention
increase Nfid3
activation. In yet an additional embodiment, the methods of present invention
increase IL-6. In
another embodiment, the methods of the present invention increase IL-10. In
yet an additional
embodiment, the methods of present invention increase IL-29. In another
embodiment, the
methods of the present invention increase IFNa. As a further embodiment, the
methods of the
present invention decrease STAT3 phosphorylation.
[00127] The present invention will be further illustrated and/or
demonstrated in the
following Examples, which is given for illustration/demonstration purposes
only and is not
intended to limit the invention in anyway.
Example 1
[00128] The objective of this study was to evaluate the distribution of an
infused TLR9
agonist, SD-101, in and around a primary liver tumor. In particular, the study
was conducted on a
novel swine model that forms liver tumors in situ. To recapitulate primary
liver tumor
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development, biopsies of liver tissue were collected from the swine and then
the cells were
exposed to a vector to induce cancerous growth. These cells were subsequently
engrafted into
the liver tissue by local needle injection and allowed to develop tumors
approximately 2 cm in
diameter.
[00129] The TLR9 agonist SD-101 sequence oligo was synthesized and
conjugated to the
IRD800CW (ex. 767 nm, em.791nm) fluorophore. Then, the IRD800CW-SD-101 (1 ml
at 2.5
nmol) was mixed with SD-101 (0.3 ml, containing 4 mg SD-101 drug product) into
9 ml of
sterile saline solution to produce a 10.3 ml total volume for infusion. The
solution was infused
via HAT using a PEDD device, i.e., the TriNav .
[00130] The Seldinger technique was used to gain access through the
femoral artery of the
subject swine. A 5F introducer sheath was secured at the site. A 5F
angiographic catheter was
used to perform angiography to identify hepatic arterial anatomy. A 1.5- to
3.5-mm diameter
vessel feeding the entire left lateral, left medial, right medial, or right
lateral lobe containing the
tumor was then selected. The TriNav was then tracked into the target vessel
location.
[00131] The syringe containing the solution was then placed into a syringe
pump and
delivered at a rate of 2 ml/min through the TriNav . After the first 4 ml of
solution were infused,
a 1 ml high-pressure bolus was conducted at a rate of 2 cc/sec for a duration
of 0.5 seconds. The
remainder of the solution was then administered at 2 ml/min.
[00132] Normal physiologic conditions were maintained for 60 minutes,
after which time
the swine were euthanized and their livers were removed. Each lobe of the
liver was separated
and near-IR imaging with a Pearl Trilogy Imaging System was performed to
identify patterns of
drug uptake. Each lobe was then cut into 1 cm thick sections and separately
imaged (85[tm
resolution, 700 nm, 800 nm, and white light channels) on both tissue faces
using the Pearl
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system. The full liver volume was analyzed to visualize the distribution of
fluorescently-labeled
SD-101, as depicted in FIG. 4. In this regard, A depicts the regions of tumor
tissue and necrosis,
B depicts the regions of growing primary tumor and surrounding normal tissue
with high uptake
of fluorescently-labeled SD-101, and C depicts normal tissue (which shows
little to no labeled
SD-101 fluorescence signal).
[00133] The study demonstrated that pressure-enabled delivery of labeled
SD-101 using a
TriNav resulted in the preferential accumulation of fluorescent compound in
the region around
the actively growing primary liver tumor periphery and surrounding normal
tissue, in which the
region is expected to contain the bulk of immune cells expressing TLR9, which
is the target of
SD-101. Further, infusions were conducted through vessels feeding an entire
lobe containing a
primary tumor, with most of the tissue in the perfused territory being normal
liver. Despite not
infusing SD-101 through specific tumor feeding vessels, the use of PEDD
resulted in preferential
distribution of SD-101 in and around the tumor, with relatively low drug
exposure in normal
liver tissue.
Example 2
[00134] In this example, infusions of a TLR9 agonist, SD-101, were
administered with
the aim of enhancing response rates to CPI therapy in patients with primary
liver cancers such as
HCC and ICC. SD-101 is a TLR9 agonist that can stimulate a variety of immune
cells, in
addition to favorably eliminating or reprogramming suppressive immune cells
that drive tumor
progression in the liver. Pressure-Enabled Drug Delivery (PEDD) via hepatic
artery infusion
(PEDD/HAI) will be applied in this study to enable effective delivery of SD-
101 to HCC tumors,
while limiting systemic exposure.
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[00135] The study has two phases, i.e. Phases lb and 2. In this regard,
the primary
objective for Phase lb is to determine the safety of and to identify the
maximum tolerated dose
(MTD) or optimal dose of PEDD/HAI of SD-101 alone, the MTD or optimal dose of
SD-101 in
combination with pembrolizumab or both nivolumab and ipilimumab in patients
with HCC or
ICC or a mixture of both HCC and ICC. Further, the secondary objective is to
assess preliminary
efficacy in terms of RECIST for immune based therapeutics (iRECIST) ORR,
modified RECIST
(mRECIST) ORR, RECIST 1.1 hepatic-specific response rate (HRR), overall
progression-free
survival (PFS), and clinical benefit (complete response [CR] + partial
response [PR] + stable
disease [SD]). With regard to Phase 2, the primary objective is to assess the
Response Evaluation
Criteria in Solid Tumors (RECIST) v1.1 overall response rate (ORR) to PEDD/HAI
of SD-101
in combination with intravenous (IV) immune checkpoint blockade. The
checkpoint regimen
used in combination with SD-101 will be chosen based on safety and response
data from Phase
lb. Separate cohorts for HCC and ICC will be enrolled. Further, the secondary
objective is to
assess the duration of response (DOR), 12-month overall survival (OS), and
safety/toxicity of the
chosen MTD or optimal dose of SD-101 in combination with CPI. Further, there
are also
exploratory objectives: (i) to assess RECIST v1.1 hepatic-specific progression-
free survival
(HPFS); (ii) to assess pathologic response following PEDD/HAI of SD-101 with
or without
systemic IV CPI infusion and correlation with imaging response scoring; (iii)
to assess the
intratumoral immunological effects of treatment on MDSC, lymphocytes, and
cytokine profiles
using paired baseline and on-treatment liver tumor and normal liver biopsies;
(iv) to assess the
peripheral immunological pharmacodynamic effects of treatment using serial
blood sampling for
circulating tumor cells (CTC), circulating cytokines, and other immunologic
correlatives; (v) to
assess changes from baseline in ECOG PS over time; (vi) to assess changes from
baseline in
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quality of life using the European Organization for the Research and Treatment
of Cancer
Quality of Life Questionnaire for Cancer (EORTC-QLQ-C30) instrument.
[00136] The overall design for the study can be found in FIG. 5. The study
is open-label,
multicenter, and nonrandomized.
[00137] As described in further detail below, in Phase lb, escalating
doses of SD-101 can
be administered alone (Cohort A), together with pembrolizumab (Cohort B), or
together with
combined ipilimumab and nivolumab (Cohort C). Cohorts B and C will begin one
dose level
below the MTD or optimal dose from Cohort A to optimize safety when adding CPI
to SD-101.
Cohort B will not begin until completion of the DLT window for the final
patient in Cohort A
(Cohort B will proceed concurrently with the Cohort A expansion). Cohort C
will not begin until
completion of the DLT window for the final patient in Cohort B. A standard 3 +
3 dose-
escalation design will be employed to determine the MTD.
[00138] Following the first SD-101 infusion for each patient in Phase lb,
an overnight
in-hospital observation or admission is required. If the first SD-101 dose is
well tolerated, further
overnight observation or admission is at the discretion of the treating
physician for subsequent
SD-101 infusions. If subsequent infusions are performed on an outpatient
basis, the patient will
be observed for a minimum of 6 hours post infusion before being discharged, if
clinically stable.
If there are any events > Grade 2 related to SD-101 PEDD/HAI that required in-
patient therapy
following the first infusion, the patient will be kept for overnight
observation or admission
following each subsequent SD-101 infusion.
[00139] Following determination of the recommended MTD or optimal dose of
SD-101
for PEDD/HAI and which CPI regimen(s) are tolerated, the study will progress
to Phase 2 to
assess efficacy. Patients in Phase 2 will receive the SD-101 dose selected
from Phase lb together
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with systemic single- or double-agent checkpoint blockade. The choice of
single or dual CPI
therapy together with SD-101 for Phase 2 will consider safety data in addition
to response rates
from Cohorts B and C in Phase lb. SD-101 will be administered over 2 cycles,
with 3 weekly
doses per cycle.
Inclusion Criteria
[00140] According to an embodiment, to be included in the study, the
patient must meet
all of the following criteria for inclusion:
1. 18 years of age or older with locally advanced, metastatic or
unresectable
hepatocellular carcinoma or intrahepatic cholangiocarcinoma, with the
diagnosis
confirmed by histologic or cytologic analysis or clinical features according
to the
American Association for the Study of Liver Diseases.
2. Previously received at least 1 standard line of systemic therapy for liver
cancer and
with persistent or progressive measurable disease, as defined by RECIST
version 1.1,
that is not amenable to curative therapies.
3. Has performance status score of 0 or 1 on the ECOG scale (scores range from
0 to 5,
with higher numbers reflecting greater disability).
4. Designation of class A on the Child¨Pugh liver function scale (a three-
category scale
[A, B, or C], with C indicating the most severe compromise of liver function).
5. Adequate hematologic and organ function.
6. Has histologically or cytologically confirmed HCC or ICC with liver-only
or liver-
dominant disease. Liver-dominant will be defined as intrahepatic disease
representing
the largest fraction of disease.
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7. Able to understand the study and provide written informed consent prior to
any study
procedures.
8. Has not received prior cytotoxic chemotherapy, targeted therapy, or
external radiation
therapy within 14 days prior to screening.
9. Has not ever received prior embolic HAT therapy with permanent embolic
material.
Note: Previous embolic HAT therapy with permanent embolic material will not be
exclusionary if following this therapy, the target vessels are not occluded,
and tumors
are perfused based on the patient's screening.
10. Has no prior history of or other concurrent malignancy unless the
malignancy is
clinically insignificant, no ongoing treatment is required, and the patient is
clinically
stable.
11. Has measurable disease in the liver according to RECIST v.1.1 criteria.
12. Has a life expectancy of >3 months at screening as estimated by the
investigator.
13. Has a QTc interval <480 msec.
14. All associated clinically significant (in the judgment of the
investigator) drug-related
toxicity from previous cancer therapy must be resolved (to Grade <1 or the
patient's
pretreatment level) prior to study treatment administration (Grade 2 alopecia
and
endocrinopathies controlled on replacement therapy are allowed).
15. Has adequate organ function at screening as evidence by:
= Platelet count >100,0004LL.
= Hemoglobin >8.0 g/dL.
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= White blood cell count (WBC) >2,000/pL.
= Serum creatinine <2.0 mg/dL unless the measured creatinine clearance is
>30 mL/min calculated by Cockcroft-Gault formula.
= Total and direct bilirubin <2.0 x the upper limit of normal (ULN) and
alkaline
phosphatase <5 x ULN. For patients with documented Gilbert's disease, total
bilirubin up to 3.0 mg/dL is allowed.
= ALT and AST <5 x ULN.
= Prothrombin time/International Normalized Ratio (INR) or activated
partial
thromboplastin time (aPTT) test results at screening <1.5 x ULN (this applies
only to patients who do not receive therapeutic anticoagulation; patients
receiving
therapeutic anticoagulation should be on a stable dose for at least 4 weeks
prior to
the first dose of study intervention).
Note: Laboratory tests with exclusionary results judged by the investigator as
not
compatible with the patient's clinical status may be repeated once for
eligibility
purposes.
16. Females of childbearing potential must be nonpregnant and nonlactating, or
post-
menopausal, and have a negative serum human chorionic gonadotropin (hCG)
pregnancy test result at screening and a negative urine or serum pregnancy
test prior
to the first dose of study intervention.
= Females of childbearing potential must agree to abstain from sexual
activity with nonsterilized male partners, or if sexually active with a
nonsterilized
male partner must agree to use highly effective methods of contraception from
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screening, throughout the study and agree to continue using such precautions
for
100 days after the final dose of study intervention.
= Nonsterilized males who are sexually active with a female of childbearing
potential must agree to use effective methods of contraception and avoid sperm
donation from Day 1 throughout the study and for 30 days after the final dose
of
study intervention.
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PHASE lb
[00141] The separate Phase lb patient cohorts are as follows:
[00142] Cohort A ¨ Dose-escalation cohort of PEDD/HAI of SD-101
monotherapy (2
cycles, 1 dose per week x 3 weeks, per cycle) using a standard 3 + 3 design
followed by an
optional expansion group to identify the MTD or optimal dose of SD-101 alone
and estimate the
monotherapy response rate in HCC and ICC patients:
= Dose level 1: 4 mg (n = 3-6).
= Dose level 2: 8 mg (n = 3-6).
[00143] Enrollment of the first 2 patients at each dose level will be
staggered by at least
48 hours. Additional incremental dose levels (in increments of 4 mg) may be
added based on
safety and response data. An optional expansion group of 10 patients at the SD-
101 monotherapy
MTD or optimal dose may proceed concurrently with Cohort B.
[00144] Cohort B ¨ Standard 3 + 3 design dose re-escalation cohort of
PEDD/HAI of
SD-101 (2 cycles, 1 dose per week x 3 weeks, per cycle) together with IV
pembrolizumab 200
mg every 3 weeks (Q3W) to identify the MTD or optimal dose of SD-101 with
single-agent
pembrolizumab:
= Dose level 1: Pembrolizumab together with PEDD/HAI of SD-101 at 1 dose
level
below the MTD or optimal dose from Cohort A (i.e., MTD-1 or optimal dose-1)
(n = 3-6).
= Dose level 2: Pembrolizumab together with PEDD/HAI of SD-101 at the MTD
or
optimal dose from Cohort A (n = 3-6), or if MTD-1 or optimal dose -1 not
tolerated,
will de-escalate to MTD-2 or optimal dose-2.
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[00145] Enrollment of the first 2 patients at each dose level will be
staggered by at least
48 hours. An optional expansion group of up to 10 patients receiving SD-101
together with
pembrolizumab may proceed concurrently with Cohort C.
[00146] Cohort C ¨ Standard 3 + 3 design dose re-escalation study of
PEDD/HAI of
SD-101 (2 cycles, 1 dose per week x 3 weeks, per cycle) together with
nivolumab 1 mg/kg in
combination with ipilimumab 3 mg/kg every 3 weeks for four doses, followed by
single-agent
nivolumab 240 mg every 2 weeks to identify the MTD or optimal dose of SD-101
with dual-
agent CPI:
= Dose level 1: Nivolumab and ipilimumab together with PEDD/HAI of SD-101
at
1 dose level below the MTD or optimal dose from Cohort B (n = 3-6).
= Dose level 2: Nivolumab and ipilimumab together with PEDD/HAI of SD-101
at the
MTD or optimal dose of SD-101 from Cohort B (n = 3-6), or if MTD-1 or optimal
dose-1 not tolerated, will de-escalate to MTD-2 or optimal dose-2.
[00147] Enrollment of the first 2 patients at each dose level will be
staggered by at least
48 hours. An optional expansion group of 10 patients may be enrolled if
additional data are
needed to decide between single- and dual-agent CPI with SD-101 via PEDD/HAI
for Phase 2.
PHASE 2
[00148] Two separate cohorts will be enrolled for HCC and ICC. A two-stage
design will
be used in Phase 2 to establish whether the proportion of responses at the SD-
101 MTD or
optimal dose + single- or dual-agent CPI is sufficiently high to warrant
further testing. A two-
stage design with the smallest total sample will be used for each tumor type.
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Duration of Administration
Duration of SD-101 administration (for participants in Phase lb and Phase 2):
[00149] Phase lb Cohorts A, B, C, and Phase 2- Up to 6 doses (maximum of 2
cycles of
SD-101, 3 weekly doses per cycle). Fewer doses or cycles of SD-101 may be
administered based
on toxicity or tolerability. All patients who have presence of measurable
disease at baseline, one
post-baseline tumor assessment, received at least 1 dose of treatment, no
violation of key
inclusion or exclusion criteria will be considered evaluable. However,
patients who enrolled in
violation of key inclusion or exclusion criteria will be considered major
protocol violations and
will not be considered evaluable.
Duration of CPI administration
Phase lb, Cohort A:
= Not applicable.
Phase lb, Cohort B and optional expansion cohort:
= Up to 6 months of pembrolizumab 200 mg Q3W.
Phase lb, Cohort C and optional expansion cohort:
= IV nivolumab 1 mg/kg Q3W for 4 doses then 240 mg every 2 weeks (Q2W) for
up to
12 months.
= IV ipilimumab 3 mg/kg Q3W for 4 doses.
Phase 2:
= CPI regimen as determined by Phase lb data for up to 6 months.
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Phase 1, Cohort B and optional expansion cohort:
= Up to twelve months of nivolumab 480 mg Q4W.
Phase 1, optional Cohort B 1:
= Systemic IV ipilimumab 3 mg/kg Q3W for 4 doses.
Phase 1, Cohort C and optional expansion cohort:
= Systemic IV nivolumab 1 mg/kg Q3W for 4 doses then 480 mg/kg Q4W for up
to
twelve months and (ii) systemic IV ipilimumab 3 mg/kg Q3W for 4 doses.
Phase lb:
= CPI regimen as determined by Phase 1 data for up to twelve months.
Interventions Administered
[00150] The interventions and planned dose levels are summarized in Table
2 below.
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Table 2
Intervention SD-101 Keytruda Opdivo Yervoy
Name (pembrolizumab) (nivolumab) (ipilimumab)
Type Drug (ODN) Biologic (antibody) Biologic Biologic
(antibody) (antibody)
Dose Solution Solution for injection Solution for Solution
for
Formulation injection injection
Unit Dose 13.4 mg/mL 100 mg/4 mL 40 mg/4 mL 5 mg/mL
Strength(s) 100 mg/10mL
240 mg/24mL
Dosage 4 or 8 mg 200 mg 1 mg/kg IV 3 mg/kg IV
Level(s) 240 mg IV
Route of Intravascular IV IV IV
Administration injection by
a PEDD/HAI
over 10-60
minutes
Use Experimental Background Background Background
intervention intervention intervention
IMP and CPI IMP HCC FDA approved HCC FDA HCC FDA
ICC IMP approved approved
ICC IMP ICC IMP
Sourcing TriSalus Commercial ¨ site Commercial ¨ site Commercial
¨
supply supply site supply
Packaging and Single-use vialb Single-dose vial Single-dose vials Single-
dose
Labeling vials
Abbreviations: HAI = hepatic artery infusion; IlVIP = investigational
medicinal product; IV =
intravenous; ODN = oligodeoxynucleotide; PEDD = Pressure-Enabled Drug Delivery
device.
a Each segmental, sectoral, or lobar infusion must be completed within 60
minutes to ensure that
the SD-101 does not remain in the TriNav device for longer than that time.
This does not limit
overall procedure time.
Vial will be discarded following dose preparation for a single patient. In no
instance will more
than one dose be drawn from one vial.
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PEDD/HAI of SD-101
[00151] The SD-101 solution can be infused via the hepatic arterial system
using a PEDD
device, e.g., the TriNav . Vascular access may be achieved using the femoral
or radial approach.
Hemangiomata, shunting vessels, or other vascular lesions in the liver that
may interfere with
therapeutic delivery may be embolized at the discretion of the treating
interventional radiology
specialist. For the SD-101 infusion procedures, the drug will be prepared in
the local pharmacy
and delivered to the interventional radiology suite in a 50-mL syringe
(therapeutic dose) and a
100-mL vial containing the volume necessary for the therapeutic flush (10-mL),
both at the
therapeutic concentration. The pharmacy can be notified 1 day in advance of
the planned
infusion time and again when the patient is on the table. The PEDD device, the
TriNav , will be
advanced into the target vessels.
[00152] In one embodiment, the 50 mL volume to be administered is
allocated by per
segment or sector of the liver. In an embodiment, the 50-mL therapeutic dose
can be allocated as
follows: 3 x 10 mL infusions into target vessels in the right hepatic lobe and
2 x 10 mL infusions
into target vessels in the left hepatic lobe. Further, the distribution of the
10-mL aliquots may be
adjusted based on the location of measurable disease and target vessel
diameter. In an
embodiment, the SD-101 infusion is expected to last approximately 10-60
minutes. For example,
the infusion time can be approximately 25 minutes. Further, in an embodiment,
the overall
interventional procedure can last between 30-80 minutes. This involves all the
handling time
between infusions in different locations.
Tumor Response Evaluations
[00153] All patients will undergo imaging with magnetic resonance imaging
(Mill) or
CT to assess disease in the liver and other sites, as well as liver biopsies
and assays of CTC,
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circulating cytokines, and other immunologic correlatives. Tumor response will
be measured
radiographically using standard RECIST v1.1 criteria. Official response
scoring (per RECIST
v1.1) will be preliminarily assessed on Day 84. Additional response
assessments will be obtained
at Day 168 to confirm earlier scoring in the event of pseudo-progression.
Imaging procedures
will occur every 90 days thereafter. Hepatic imaging using Mill with Eovist
contrast should be
used whenever possible. Local imaging reads will be utilized for response
assessment during
Phase lb and Phase 2. Independent central review for response assessment may
be performed
during Phase 2.
[00154] Up to 4 liver biopsies will be performed:
= A baseline biopsy will be obtained on Day 1 before the first infusion of
SD-101 in
addition to a post infusion biopsy on Day 1. A pre infusion biopsy will be
performed
at the beginning of the second cycle of SD-101 (before SD-101 Infusion #4),
and the
final biopsy procedure occurs at Day 100.
= Pathologic response will be assessed based on review by the local site
pathologist
with scoring of necrosis and fibrosis within tumor and normal tissue samples.
Quality of Life
[00155] The ECOG PS scale and EORTC-QLQ-C30 questionnaire can be used to
assess
overall patient status and quality of life.
Pharmacokinetics
[00156] Blood samples will be collected to characterize SD-101 systemic
exposure after
PEDD/HAI. No sampling or testing will be done for pembrolizumab, nivolumab or
ipilimumab
concentrations.
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= Phase lb: Serial venous blood samples will be collected for measurement
of plasma
SD-101 concentrations before dosing and after the end of each dose for each
dose
level in Cohorts A, B, and C. Samples times may be adjusted based on results
observed after initial doses for Cohort A in Phase lb of the study.
= Phase 2: If the concentrations are mostly below the lower limit of
quantification of
the assay in Phase lb, these measurements may be omitted in Phase 2.
[00157] Tumor levels of SD-101 will be measured in the pre- and post-
infusion biopsy
specimens obtained on: Day 1 and Day 57 (pre-infusion only) for Cohorts A, B,
and C.
[00158] Each plasma sample can be divided into 2 aliquots of approximately
2-3 mL
each (1 for SD-101 measurement and 1 for back-up). Samples collected for
analyses of SD-101
may also be used to evaluate safety or efficacy aspects related to concerns
arising during or after
the study.
Pharmacodynamics
[00159] Blood samples can be collected for the measurement of CTC,
circulating
cytokines, and other immunologic correlatives including IFN-a and IFN-y
related gene
signatures, which may be more informative than pharmacokinetic assessments for
this class of
therapeutic.
Safety
[00160] Safety assessments include adverse events (AEs), clinical
laboratory testing, vital
signs, physical examinations, and electrocardiograms (ECGs).
[00161] The following are considered DLTs when observed during Phase lb
within
2 weeks after the last SD-101 dose in Cycle 1 and are considered attributable
to study
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intervention (SD-101 or CPI therapy) and/or the TriNav device. Note, however,
that the same
adjustment or stopping rules will apply for any DLT (defined below) that may
arise during the
infusion period of Cycle 2:
= > Grade 3 cytokine release syndrome (CRS) per National Cancer Institute
(NCI)
Common Terminology Criteria for Adverse Events (CTCAE) Version 5Ø
= Autoimmune AE > Grade 3 per NCI CTCAE.
= Allergic reaction AE > Grade 3 per NCI CTCAE.
= Grade 4 hematologic AE per NCI CTCAE that does not recover to < Grade 2
within 7
days.
= Grade 4 AE per NCI CTCAE in any organ system.
[00162] Patients who develop a DLT will be permanently discontinued from
study
interventions. The patient can be treated according to clinical practice and
monitored for
resolution of the toxicity.
[00163] SD-101 and/or CPI therapy will be permanently discontinued for
severe or life-
threatening infusion-related reactions. Dose interruptions, delays, or
discontinuation of SD-101
and/or CPI therapy is required when a patient has a Grade 3 or higher immune-
mediated
reaction. Discontinuation of SD-101 and/or CPI therapy for abnormal liver
tests is required when
a patient meets one of the conditions outlined below or in the presence of
abnormal liver
chemistries not meeting protocol-specified stopping rules if the investigator
believes that it is in
best interest of the patient.
= Patient is clinically jaundiced.
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= Patient has evidence of coagulopathy.
= Patient has clinical evidence of portal hypertension including but not
limited to
ascites or variceal bleeding.
[00164] All patients can be followed in this study for safety for at least
6 months after the
start of treatment and 1 year for disease status.
[00165] Patients who discontinue study treatment for reasons other than
disease
progression (e.g. toxicity, withdrawal of consent) can continue to undergo
scheduled tumor
assessments every 90 days until the patient dies, experiences disease
progression (intra- or
extrahepatic), or initiates further systemic cancer therapy, whichever occurs
first.
Rescue Medication and Therapy
[00166] The study site will supply immunomodulatory rescue medication that
will be
obtained locally. The following rescue medications may be used:
Medications
= IL 6 receptor antibody Tocilizumab 4-8 mg/kg systemic IV over 60 minutes
for CRS,
may repeat as clinically indicated.
= Methylprednisolone 2 mg/kg systemic IV bolus followed by 0.5 mg/kg IV
every
6-12 hours for CRS Grade >2, or neurologic dysfunction. The first dose can be
given
without consultation with the investigator or designee; however, the
subsequent doses
must be given after the consultation with the study investigator or designee.
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= Consider 1 to 2 doses of anti-TNFa agents (infliximab or etanercept). The
benefits are
not known, but since TNFa may rise acutely, it is worth considering early in
the
disease process.
= Etanercept 25 mg SC twice a week for 2 doses, given 3 to 4 days apart
(0.4 mg/kg
twice a week, maximum of 25 mg per dose.
= Infliximab dose 10 mg/kg systemic IV weekly x 2 doses.
Interventions
= Endoscopic cholangiography and stent placement.
= Percutaneous cholangiography and stent placement.
[00167] Although the use of rescue medications is allowable at any time
during the study,
the use of rescue medications should be delayed, if possible and clinically
appropriate, for at
least 6 hours following the administration of study intervention. The date and
time of rescue
medication administration, as well as the name and dosage regimen of the
rescue medication
must be recorded.
[00168] Adverse events clearly due to disease progression, unrelated to
study drug, or
expected for the eligible patient population of the study are not considered
DLTs.
Assessment for Cytokine Release Syndrome
[00169] The Investigator, or designee, will assess each patient for the
presence of CRS.
CRS grading will be determined based on the NCI CTCAE v5.0 and managed as
shown in Table
3.
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Table 3: Grading Criteria for Cytokine Release Syndrome
CRS Manifestation Management
Severity
Grade 1 Fever (>38 C)a with or without Antipyretic and hypothermia blanket as
needed
constitutional symptoms, and/or for fever
ALT/AST >ULN-3xULN, Assess for infection
and/or
IV fluids as needed
Alkaline phosphatase >ULN-
2.5xULN, and/or Symptomatic management of constitutional
symptoms and organ toxicities, as needed
Bilirubin >ULN-1.5xULN
Grade 2 Hypotension (SBP <90 mmHg Fever: Manage as per Grade 1 guidelines
or <20% baseline) responding to
Hypotension: IV fluid bolus of 500-1000 mL
fluids, and/or
NS, repeat as necessary to maintain SBP >90
Hypoxia responding to <40% mmHg
oxygen, and/or
If SBP refractory to NS boluses, consider the
ALT/AST >3-5xULN, and/or use of corticosteroids.
Alkaline phosphatase >2.5- If hypotension persists after IV fluid
boluses and
5xULN, and/or corticosteroids, consider:
Bilirubin >1.5-3 xULN Transfer to ICU, vasopressin, 2D
echocardiogram
Hypoxia: Use supplemental oxygen as necessary
to keep oxygen saturation >92%
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CRS Manifestation Management
Severity
Grade 3 Hypotension managed with one Patient should be in the ICU:
pressor, and/or
Fever: Manage as per Grade 1 CRS
Hypoxia requiring >40%
Hypotension:
oxygen, and/or
IV fluid boluses as needed as in Grade 2 CRS
AST/ALT/Alkaline phosphatase
>5-20xULN, and/or Vasopressors as needed
Bilirubin >3-10 xULN Consider tocilizumab 8 mg/kg (maximum 800
mg per dose) IV for up to 3 doses in a 24-hour
period (maximum 4 doses total)
Obtain echocardiogram if not already performed
Hypoxia:
Use supplemental oxygen (>6 L/min) including
high-flow oxygen delivery and non-invasive
positive pressure ventilation as needed
Use corticosteroids, IL-6 receptor antagonist as
above and supportive care
Grade 4 Life-threatening consequences; Fever: Manage as per Grade 1 CRS
urgent intervention indicated
and/or ,
Hypotension:
IV fluids, IL-6 receptor antagonist,
ALT/AST/Alkaline phosphatase
>20xULN, and/or vasopressors, and hemodynamic monitoring
as
in Grade 3
Bilirubin >10 xULN
High-dose corticosteroids
Hypoxia:
Positive pressure/mechanical ventilation
Use high-dose corticosteroids, IL-6 receptor
antagonist and supportive care
Abbreviations: 2D = 2 dimensional; ALT = alanine aminotransferase; AST =
aspartate
aminotransferase; ASTCT = American Society for Transplantation and Cellular
Therapy; CRS =
cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse
Events;
ICU = intensive care unit; IL=interleukin; IV = intravenous; NCI=National
Cancer Institute; NS
= normal saline; SBP = systolic blood pressure; ULN = upper limit of normal
'Fever is defined as temperature >38 C not attributable to any other cause.
Source: Adapted from the NCI CTCAE and ASTCT (Lee DW, Santomasso BD, Locke FL,
Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine
release
syndrome and neurologic toxicity associated with immune effector cells. Biol
Blood Marrow
Transplant. 2019;25;625-38).
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Imaging
[00170] Extent of disease will be measured radiographically at the time
points for Cohort
A, Cohort B, and Cohort C. Screening assessments must include an MRI of the
abdomen and
pelvis (with oral/IV Eovist contrast unless contraindicated) and a brain scan
(CT with IV contrast
or MM). A spiral CT scan of the chest should be obtained in addition to the
MRI of the abdomen
and pelvis. If an MRI is medically contraindicated or at the discretion of the
physician, a CT scan
of the chest, abdomen, and pelvis may be performed using triple phase IV
contrast. If a site is
unable to perform a triple phase CT of the chest, abdomen, pelvis, they may
perform the CT of
the chest, abdomen, pelvis with IV contrast and obtain arterial phase and
portal venous phase
imaging. If a PET/CT scan is performed (not required), the CT portion of the
study must be
consistent with the standards for a full-contrast CT scan. Liver metastasis
responses will be
assessed on abdominal CT or MM, while extrahepatic lesions will be assessed on
whole body
PET/CT scans or CT/MM scans that cover the chest, abdomen, and pelvis. Hepatic
imaging
using MRI with Eovist contrast should be used whenever possible for assessment
of liver tumors.
The same imaging method used at screening must be used throughout the study.
[00171] Any evaluable or measurable disease must be documented at
screening and re-
assessed at each subsequent tumor evaluation. For patients with measurable
disease, response
will be assessed per RECIST v1.1. Local imaging reads will be utilized for
response assessment
during Phase lb. Independent Central Review (ICR) for response assessment may
be considered
during Phase 2.
[00172] At the investigator's discretion, imaging may be performed at any
time if PD is
suspected. In addition, mRECIST and iRECIST assessments will be performed for
secondary
endpoint data collection but will not be incorporated into official response
scoring.
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ECOG Performance Status
[00173] The ECOG PS scale will be used to assess how the disease is
affecting the
patient's daily living activities and ability to take care of themselves. At
each specified time
point, qualified site personnel will rate the patient according to the
following scale:
= Fully active, able to carry on all predisease performance without
restriction
= Restricted in physically strenuous activity but ambulatory and able to
carry out work
of a light or sedentary nature, e.g. light house work, office work
= Ambulatory and capable of all self-care but unable to carry out any work
activities;
up and about more than 50% of waking hours
= Capable of only limited self-care; confined to bed or chair more than 50%
of waking
hours
= Completely disabled; cannot carry on any self-care; totally confined to
bed or chair
= Dead
[00174] Changes, i.e. worsening, will not be documented as AEs unless
reported during
the nondirected questioning for AEs.
RECIST v1.1 Definitions
[00175] Measurable disease ¨ The presence of at least 1 measurable lesion.
If the
measurable disease is restricted to a solitary lesion, its neoplastic nature
should be confirmed by
cytology/histology.
[00176] Measurable lesions ¨ Lesion that can be accurately measured in at
least 1
dimension with longest diameter >10 mm (CT scan slice thickness <5 mm).
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[00177] Nonmeasurable lesions ¨ All other lesions, including small lesions
(longest
diameter <10 mm), as well as truly nonmeasurable lesions (such as
leptomeningeal disease,
ascites, pleural/pericardial effusion, inflammatory breast disease,
lymphangitic involvement of
skin or lung, abdominal masses that are not measurable by reproducible imaging
techniques).
Baseline Documentation
[00178] All measurable lesions up to a maximum of 2 lesions per organ and
5 lesions in
total, representative of all involved organs should be identified as target
lesions and recorded and
measured at baseline.
[00179] Target lesions should be selected on the basis of their size
(lesions with the
longest diameter) and their suitability for accurate repeated measurements by
consistent imaging
techniques.
[00180] A sum of the longest diameter (LD) for all target lesions (non-
nodal) will be
calculated and reported as the baseline sum LD. The baseline sum LD will be
used as reference
by which to characterize the objective tumor response in the measurable
dimension of the
disease.
[00181] All other lesions (or sites of disease) should be identified as
nontarget lesions
and should also be recorded at baseline. Measurements of these lesions are not
required, but the
presence or absence of each should be noted throughout follow-up.
Evaluation of Target Lesions
[00182] Complete Response (CR): Disappearance of all target lesions
[00183] Partial Response (PR): At least a 30% decrease in the sum of the
LD of target
lesions, taking as reference the baseline sum LD.
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[00184] Progressive Disease (PD): At least a 20% increase in the sum of
the LD of target
lesions, taking as reference the smallest sum LD recorded since the treatment
started or the
appearance of 1 or more new lesions. The sum must demonstrate an absolute
increase on 5 mm.
[00185] Stable Disease (SD): Neither sufficient shrinkage to qualify for
PR nor sufficient
increase to qualify for PD, taking as reference the smallest sum LD since the
treatment started.
Evaluation of Nontarget Lesions
[00186] Complete Response (CR): Disappearance of all nontarget lesions
[00187] Non-CR/Non-PD: Persistence of one or more nontarget lesion(s)
[00188] Progressive Disease (PD): Unequivocal progression of existing
nontarget lesions,
and/or the appearance of one or more new lesions.
Assessment of Response
[00189] Response will be assessed at the time points for Cohort A, Cohort
B, and Cohort
C according to Table 4:
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Table 4: Assessment of Response per RECIST v1.1
Time-Point Response
Target lesions Nontarget lesions New Lesions Overall response
CR CR No CR
CR Non-CR/non-PD No PR
PR Non-PD No PR
SD Non-PD No SD
PD Any Yes or No PD
Any PD Yes or No PD
Any Any Yes PD
Abbreviations: CR = complete response; PD = progressive disease; PR = partial
response; SD =
stable disease.
Duration of overall response
[00190] The duration of overall response is measured from the time
measurement criteria
are met for CR or PR (whichever is first recorded) until the first date that
recurrent or PD is
objectively documented (taking as reference for PD the smallest measurements
recorded since
the treatment started). The duration of overall CR is measured from the time
measurement
criteria are first met for CR until the first date that PD is objectively
documented. Duration of
SD: Stable disease is measured from the start of the treatment until the
criteria for progression
are met, taking as reference the smallest sum of measurements recorded since
the treatment
started, including the baseline measurements.
Overall Survival
[00191] For all patients, OS will be calculated from the date of
enrollment to the time of
death. Patients who are still alive prior to the data cutoff for final
efficacy analysis, or who
dropout prior to study end, will be censored at the day they were last known
to be alive.
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Progression-Free Survival
[00192] For all patients, PFS will be calculated from the date of
enrollment to the time of
CT scan documenting relapse (or other unambiguous indicator of disease
development), or date
of death, whichever occurs first. Patients who have no documented relapse and
are still alive
prior to the data cutoff for final efficacy analysis, or who dropout prior to
study end, will be
censored at the date of the last radiological evidence documenting absence of
relapse.
Modified RECIST (mRECIST)
[00193] mRECIST definitions for hepatocellular carcinoma are as follows:
[00194] Complete Response (CR) = Disappearance of any intratumoral
arterial
enhancement in all target lesions
[00195] Partial Response (PR) = At least a 30% decrease in the sum of
diameters of
viable (enhancement in the arterial phase) target lesions, taking as reference
the baseline sum of
the diameters of target lesions
[00196] Stable Disease (SD) = Any cases that do not qualify for either PR
or progressive
disease
[00197] Progressive Disease (PD) = An increase of at least 20% in the sum
of the
diameters of viable (enhancing) target lesions, taking as reference the
smallest sum of the
diameters of viable (enhancing) target lesions recorded since treatment
started
[00198] Response will also be assessed by mRECIST as shown in Table 5.
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Table 5: Assessment of Response per mRECIST
Target Lesions Nontarget Lesions New Lesions Overall Response
CR CR No CR
CR IR/SD No PR
PR Non-PD No PR
SD Non-PD No SD
PD Any Yes or No PD
Any PD Yes or No PD
Any Any Yes PD
Abbreviations: CR = complete response; PR = partial response; IR = incomplete
response; SD =
stable disease; PD = progressive disease.
Source: Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for
hepatocellular
carcinoma. Sem Liver Dis. 2010; 30:52-60.
RECIST 1.1 for Immune Based Therapeutics (iRECIST)
[00199] Response will also be assessed by iRECIST as shown in Table 6. In
brief, the
main differences between RECIST and iRECIST are explained in Seymour et al
2017 as follows:
"The principles used to determine objective tumor response are largely
unchanged from RECIST
1.1, but the major change for iRECIST is the concept of resetting the bar if
RECIST 1.1
progression is followed at the next assessment by tumor shrinkage. iRECIST
defines iUPD on
the basis of RECIST 1.1 principles; however iUPD requires confirmation, which
is done on the
basis of observing either a further increase in size (or in the number of new
lesions) in the lesion
category in which progression was first identified in (i.e., target or
nontarget disease), or
progression (defined by RECIST 1.1) in lesion categories that had not
previously met RECIST
1.1 progression criteria. However, if progression is not confirmed, but
instead tumor shrinkage
(compared with baseline), which meets the criteria of iCR, iPR or iSD, then
the bar is reset so
that iUPD needs to occur again (compared with nadir values) and then be
confirmed (by further
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growth) at the next assessment for iCPD to be assigned. If no change in tumor
size or extent
from iUPD occurs, then the timepoint response would again be iUPD. This
approach allows
atypical responses, such as delayed responses that occur after
pseudoprogression, to be
identified, further understood, and better characterized."
Table 6: Assessment of Response per iRECIST
Time-Point Response
Target Nontarget New
lesions* lesions* Lesions* No prior
Prior iUPD**'***
iUPD**
iCR iCR No iCR iCR
iCR Non- No iPR iPR
iCR/non-
iUPD
iPR Non- No iPR iPR
iCR/non-
iUPD
iSD Non- No iSD iSD
iCR/non-
iUPD
iUPD with iUPD with Yes NA NLs confirms iCPD if NLs were
no change no change previously identified and
increase in
OR decrease OR size (>5 mm in SOM for NLT or
any
from last TP decrease increase for NLNT) or number. If
no
from last change in NLs (size or number)
from
TP last TP, remains iUPD
iSD, iPR, iUPD No iUPD Remains iUPD unless iCPD
iCR confirmed based on further
increase
in size of NT disease (need not meet
RECIST 1.1 criteria for unequivocal
PD)
iUPD Non- No iUPD Remains iUPD unless iCPD
iCR/non- confirmed based on:
iUPD
further increase in SOM of at least 5
mm, otherwise remains iUPD
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Time-Point Response
Target Nontarget New
lesions* lesions* Lesions* No prior
Prior iUPD**;***
iUPD**
iUPD iUPD No iUPD Remains iUPD unless iCPD
confirmed based on further increase
in:
previously identified target lesion
iUPD SOM >5 mm or
NT lesion iUPD (prior assessment -
need not be unequivocal PD)
iUPD iUPD Yes iUPD Remains iUPD unless iCPD
confirmed based on further increase
in:
previously identified target lesion
iUPD >5 mm or
previously identified NT lesion iUPD
(need not be unequivocal) or
size or number of new lesions
previously identified
Non- Non- Yes iUPD Remains iUPD unless iCPD
iUPD/PD iUPD/PD confirmed based on:
increase in size or number of new
lesions previously identified
Abbreviations: CR=complete response; iCPD = confirmed immune PD; iCR = immune
complete response; iPR =immune partial response; iRECIST=Response Evaluation
Criteria in
Solid Tumors for immune based therapeutics; iSD = immune stable disease; iUPD
= immune
unconfirmed PD; NA=not applicable; NIL = new lesions; NLT=new lesion target;
NLNT=new
lesion nontarget; NT = nontarget; PD = progressive disease; PR=partial
response;
RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease; SOM =
sum of
measures; TP = time point
* Using RECIST 1.1 principles. If no pseudoprogression occurs, RECIST 1.1 and
iRECIST
categories for CR, PR and SD would be the same. ** in any lesion category. ***
previously
identified in assessment immediately prior to this TP.
[00200] The foregoing merely illustrates the principles of the disclosure.
Various
modifications and alterations to the described embodiments will be apparent to
those skilled in
the art in view of the teachings herein. It will thus be appreciated that
those skilled in the art will
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be able to devise numerous systems, arrangements, and procedures which,
although not
explicitly shown or described herein, embody the principles of the disclosure
and can be thus
within the spirit and scope of the disclosure. Various different exemplary
embodiments can be
used together with one another, as well as interchangeably therewith, as
should be understood by
those having ordinary skill in the art. In addition, certain terms used in the
present disclosure,
including the specification, can be used synonymously in certain instances,
including, but not
limited to, for example, data and information. It should be understood that,
while these words,
and/or other words that can be synonymous to one another, can be used
synonymously herein,
that there can be instances when such words can be intended to not be used
synonymously.
Further, to the extent that the prior art knowledge has not been explicitly
incorporated by
reference herein above, it is explicitly incorporated herein in its entirety.
All publications
referenced are incorporated herein by reference in their entireties.
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