U.S. patent application number 16/563317 was filed with the patent office on 2019-12-26 for treatment of lung cancer using an anti-fucosyl-gm1 antibody.
The applicant listed for this patent is Bristol-Myers Squibb Company. Invention is credited to Jeffrey R. JACKSON.
Application Number | 20190389965 16/563317 |
Document ID | / |
Family ID | 54261114 |
Filed Date | 2019-12-26 |
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United States Patent
Application |
20190389965 |
Kind Code |
A1 |
JACKSON; Jeffrey R. |
December 26, 2019 |
TREATMENT OF LUNG CANCER USING AN ANTI-FUCOSYL-GM1 ANTIBODY
Abstract
This disclosure provides a method for treating a subject
afflicted with a lung cancer, which method comprises administering
to the subject a therapeutically effective amount of an antibody or
an antigen-binding portion thereof that specifically binds to
Fucosyl-GM1.
Inventors: |
JACKSON; Jeffrey R.;
(Schwenksville, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bristol-Myers Squibb Company |
Princeton |
NJ |
US |
|
|
Family ID: |
54261114 |
Appl. No.: |
16/563317 |
Filed: |
September 6, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15512522 |
Mar 17, 2017 |
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PCT/US2015/051827 |
Sep 24, 2015 |
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16563317 |
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62055276 |
Sep 25, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 39/39558 20130101;
C07K 2317/41 20130101; A61P 35/00 20180101; C07K 2317/33 20130101;
C07K 16/3084 20130101; C07K 16/3023 20130101; A61K 2039/505
20130101; C07K 16/46 20130101 |
International
Class: |
C07K 16/30 20060101
C07K016/30; C07K 16/46 20060101 C07K016/46; A61K 39/395 20060101
A61K039/395 |
Claims
1. A method for treating a subject afflicted with a lung cancer,
comprising administering to the subject a therapeutically effective
amount of a monoclonal antibody or an antigen-binding portion
thereof that binds specifically to Fucosyl-GM1, wherein the
antibody is administered at a dose ranging from 10 to 2000 mg once
every 1, 2, 3 or 4 weeks.
2. The method of claim 1, wherein the lung cancer is small cell
lung cancer (SCLC).
3. The method of claim 1, wherein the antibody cross-competes with
BMS-986012 for binding to Fucosyl-GM1, and further wherein
BMS-986012 comprises heavy and light chain variable regions
comprising the sequences set forth in SEQ ID NOs: 3 and 4,
respectively.
4. The method of claim 1, wherein the antibody is a chimeric,
humanized or human monoclonal antibody or a portion thereof.
5. The method of claim 4, wherein the antibody comprises a human
IgG1 or IgG4 heavy chain constant region.
6. The method of claim 3, wherein the antibody or antigen-binding
portion thereof comprises: (a) a heavy chain variable region CDR1
comprising SEQ ID NO: 5 (b) a heavy chain variable region CDR2
comprising SEQ ID NO: 6; (c) a heavy chain variable region CDR3
comprising SEQ ID NO: 7; (d) a light chain variable region CDR1
comprising SEQ ID NO: 8; (e) a light chain variable region CDR2
comprising SEQ ID NO: 9; and (f) a light chain variable region CDR3
comprising SEQ ID NO: 10.
7. The method of claim 6, wherein the antibody or antigen-binding
portion thereof comprises heavy and light chain variable regions
comprising the sequences set forth in SEQ ID NOs: 3 and 4,
respectively.
8. The method of claim 1, wherein the antibody is
non-fucosylated.
9. The method of claim 1, wherein the antibody is administered at a
dose ranging from 20 to 1000 mg once every 3 weeks.
10. The method of claim 1, wherein the method comprises at least
one treatment cycle of three weeks.
11. The method of claim 10, wherein the method comprises at least
four treatment cycles of three weeks.
12. The method of claim 11, wherein the antibody is administered on
Days 1, 22, 43, and 64.
13. The method of claim 1, wherein the antibody is administered
according to a dosing regimen selected from the group consisting
of: (a) about 20 mg of the antibody every 3 weeks; (b) about 70 mg
of the antibody every 3 weeks; (c) about 160 mg of the antibody
every 3 weeks; (d) about 400 mg of the antibody every 3 weeks; and
(e) about 1000 mg of the antibody every 3 weeks.
14. The method of claim 13, wherein the antibody is administered
according to a dosing regimen selected from the group consisting
of: (a) 20 mg of the antibody every 3 weeks; (b) 70 mg of the
antibody every 3 weeks; (c) 160 mg of the antibody every 3 weeks;
(d) 400 mg of the antibody every 3 weeks; and (e) 1000 mg of the
antibody every 3 weeks.
15. The method of claim 1, wherein the antibody is formulated for
intravenous administration.
16. The method of claim 1, wherein the subject has previously
received an initial anti-cancer therapy.
17. The method of claim 16, where the subject has a relapsed or
refractory lung cancer.
18. The method of claim 1, wherein the method produces at least one
therapeutic effect selected from a reduction in size of a tumor,
reduction in number of metastatic lesions over time, complete
response, partial response, and stable disease.
19. The method of claim 1, wherein administration of the antibody
is continued for as long as clinical benefit is observed or until
unmanageable toxicity or disease progression occurs.
20. A kit for treating a subject afflicted with a lung cancer,
comprising: (a) a dosage ranging from 10 to 2000 mg of an
anti-Fucosyl-GM1 antibody or an antigen-binding portion thereof;
and (b) instructions for using the antibody in the method of claim
1.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. application Ser.
No. 15/512,522, filed Mar. 17, 2017, which is a .sctn. 371 National
Phase of PCT/US2015/051827, filed Sep. 24, 2015, which claims
priority to U.S. Provisional Application Ser. No. 62/055,276, filed
Sep. 25, 2014, the entire contents of which are incorporated herein
by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to improved methods for
administration of antibodies to fucosyl-GM1 to treat cancer.
BACKGROUND OF THE INVENTION
[0003] Fucosyl-GM1 is a sphingolipid monosialoganglioside composed
of a ceramide lipid component, which anchors the molecule in the
cell membrane, and a carbohydrate component that is exposed at the
cell surface. Carbohydrate antigens are the most abundantly
expressed antigens on the cell surface of cancers (Feizi, T.,
Nature, 314:53-57 (1985)). In some tumor types, such as small cell
lung cancer (SCLC), initial responses to chemotherapy are
impressive, but chemo-refractory relapses rapidly follows.
Intervention with novel immunotherapeutics may succeed in
overcoming drug resistant relapse (Johnson, D. H., Lung Cancer,
12(Suppl. 3):S71-S75 (1995)). Several carbohydrate antigens, such
as gangliosides GD3 and GD2, have been shown to function as
effective targets for passive immunotherapy with MAbs (Irie, R. F.
et al., Proc. Natl. Acad. Sci., 83:8694-8698 (1986); Houghton, A.
N. et al., Proc. Natl. Acad. Sci., 82:1242-1246 (1985)).
Ganglioside antigens have also been demonstrated to be effective
targets for active immunotherapy with vaccines in clinical trials
(Krug, L.M. et al., Clin. Cancer Res., 10:6094-6100 (2004);
Dickler, M. N. et al., Clin. Cancer Res., 5:2773-2779 (1999);
Livingston, P. O. et al., J. Clin. Oncol., 12:1036-1044 (1994)).
Indeed, serum derived from SCLC patients who developed antibody
titers to Fucosyl-GM1 following vaccination with KLH conjugated
antigen, demonstrated specific binding to tumor cells and tumor
specific complement dependant cytotoxicity (CDC). Anti-Fucosyl-GM1
titer associated toxicities were mild and transient and three
patients with limited-stage SCLC were relapse-free at 18, 24, and
30 months (Krug et al., supra; Dickler et al., supra).
[0004] Fucosyl-GM1 expression has been shown in a high percentage
of SCLC cases and unlike other ganglioside antigens, Fucosyl-GM1
has little or no expression in normal tissues (Nilsson et al.,
Glycoconjugate J., 1:43-49 (1984); Krug et al., supra; Brezicka et
al., Cancer Res., 49:1300-1305 (1989); Zhangyi et al., Int. J.
Cancer, 73:42-49 (1997); Brezicka et al., Lung Cancer, 28:29-36
(2000); Fredman et al., Biochim. Biophys. Acta, 875:316-323 (1986);
Brezicka et al., APMIS, 99:797-802 (1991); Nilsson et al., Cancer
Res., 46:1403-1407 (1986)). The presence of Fucosyl-GM1 has been
demonstrated in culture media from SCLC cell lines, in tumor
extracts and serum of nude mouse xenografts and in the serum of
SCLC patients with extensive-stage disease (Vangsted et al., Cancer
Res., 51:2879-2884 (1991); Vangsted et al., Cancer Detect. Prev.,
18:221-229 (1994)). These reports provide convincing evidence for
Fucosyl-GM1 as a highly specific tumor antigen, which may be
targeted by an immunotherapeutic.
[0005] Accordingly, agents that recognize Fucosyl-GM1, and methods
of using such agents, are desired for cancer therapy.
SUMMARY OF THE INVENTION
[0006] In certain embodiments, the present invention provides a
method for treating a subject afflicted with a lung cancer,
comprising administering to the subject a therapeutically effective
amount of a monoclonal antibody or an antigen-binding portion
thereof that binds specifically to Fucosyl-GM1. In a specific
aspect, the anti-Fucosyl-GM1 antibody, or an antigen-binding
portion thereof, is administered according to a particular clinical
dosage regimen (i.e., at a particular dose amount and according to
a specific dosing schedule). In one embodiment, the subject (e.g.,
a human subject) suffers from small cell lung cancer (SCLC). In
another embodiment, the subject has previously received an initial
anti-cancer therapy. In another embodiment, the lung cancer is an
advanced, metastatic, relapsed, and/or refractory lung cancer.
[0007] In certain embodiments, the anti-Fucosyl-GM1 antibody
cross-competes with BMS-986012 for binding to Fucosyl-GM1 is
BMS-986012. Optionally, the antibody is a chimeric, humanized or
human monoclonal antibody or a portion thereof. Optionally, the
antibody comprises a human IgG1 or IgG4 heavy chain constant
region. Optionally, the antibody is non-fucosylated. To illustrate,
the antibody is BMS-986012. In one embodiment, the antibody or
antigen-binding portion thereof comprises: (a) a heavy chain
variable region CDR1 comprising SEQ ID NO: 5; (b) a heavy chain
variable region CDR2 comprising SEQ ID NO: 6; (c) a heavy chain
variable region CDR3 comprising SEQ ID NO: 7; (d) a light chain
variable region CDR1 comprising SEQ ID NO: 8; (e) a light chain
variable region CDR2 comprising SEQ ID NO: 9; and (f) a light chain
variable region CDR3 comprising SEQ ID NO: 10. In another
embodiment, the antibody or antigen-binding portion thereof
comprises heavy and light chain variable regions comprising the
sequences set forth in SEQ ID NOs: 3 and 4, respectively.
[0008] In certain embodiments, the anti-Fucosyl-GM1 antibody is
administered at a dose ranging from 10 to 2000 mg once every 1, 2,
3 or 4 weeks. For example, the antibody is administered at a dose
ranging from 20 to1000 mg once every 3 weeks. Optionally, the
method comprises at least one treatment cycle of three weeks. For
example, the method comprises at least four treatment cycles of
three weeks. To illustrate, the antibody is administered on Days 1,
22, 43, and 64. In certain specific embodiments, the antibody is
administered according to at least one of the following dosing
regimens: (a) about 20 mg of the antibody, e.g., 20 mg, every 3
weeks; (b) about 70 mg of the antibody, e.g., 70 mg, every 3 weeks;
(c) about 160 mg of the antibody, e.g., 160 mg, every 3 weeks; (d)
about 400 mg of the antibody, e.g., 400 mg, every 3 weeks; and (e)
about 1000 mg of the antibody, e.g., 1000 mg, every 3 weeks. In one
embodiment, the antibody is formulated for intravenous
administration. Preferably, administration of the antibody induces
a durable clinical response in the subject. Optionally,
administration of the antibody is continued for as long as clinical
benefit is observed or until unmanageable toxicity or disease
progression occurs. The efficacy of the treatment methods provided
herein can be assessed using any suitable means. In one embodiment,
the treatment produces at least one therapeutic effect selected
from the group consisting of reduction in size of the cancer,
reduction in number of metastatic lesions over time, complete
response, partial response, and stable disease.
[0009] In certain embodiments, the present invention provides a kit
for treating a subject afflicted with a lung cancer, the kit
comprising: (a) a dosage ranging from 10 to 2000 mg (e.g., at a
dosage from 20 to 1000 mg) of an anti-Fucosyl-GM1 antibody or an
antigen-binding portion thereof and (b) instructions for using the
antibody in the method of the present invention.
[0010] Other features and advantages of the instant invention will
be apparent from the following detailed description and examples,
which should not be construed as limiting. The contents of all
cited references, including scientific articles, newspaper reports,
GENBANK.RTM. entries, patents and patent applications cited
throughout this application are expressly incorporated herein by
reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1A shows the nucleotide sequence (SEQ ID NO: 1) and
amino acid sequence (SEQ ID NO: 3) of the heavy chain variable
region of the 7E4 human monoclonal antibody. The CDR1 (SEQ ID NO:
5), CDR2 (SEQ ID NO: 6) and CDR3 (SEQ ID NO: 7) regions are
delineated and the V, D and J germline derivations are
indicated.
[0012] FIG. 1B shows the nucleotide sequence (SEQ ID NO: 2) and
amino acid sequence (SEQ ID NO: 4) of the light chain variable
region of the 7E4 human monoclonal antibody. The CDR1 (SEQ ID NO:
8), CDR2 (SEQ ID NO: 9) and CDR3 (SEQ ID NO: 10) regions are
delineated and the V and J germline derivations are indicated.
[0013] FIG. 2 shows BMS-986012 dose response on DMS79
xenografts.
[0014] FIG. 3 is a schematic illustrating the study design of the
clinical trial CA001030.
[0015] FIG. 4 is a schematic illustrating dose escalation
algorithm
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention relates to methods for treating a lung
cancer patient comprising administering to the patient an
anti-Fucosyl-GM1 antibody (e.g., BMS-986012) or an antigen-binding
portion thereof.
[0017] BMS-986012 is a first-in-class fully human monoclonal
antibody (MAb) that specifically binds to the Fucosyl-GM1 (Fuc-GM1)
ganglioside. BMS-986012 exhibits high-affinity and dose-dependent
saturable binding to Fuc-GM1 and shows no detectable
antigen-specific binding to closely related molecule GM1.
BMS-986012 is non-fucosylated (lacking fucosylation on the Fc
domain). The absence of the fucosyl group in BMS-986012 confers
higher affinity for Fc receptors resulting in enhanced
antibody-dependent cellular cytotoxicity (ADCC). Furthermore, the
antibody was shown to mediate potent complement dependent
cytotoxicity (CDC) as well as antibody-dependent cellular
phagocytosis (ADCP). See, for example, WO 2007/067992, the content
of which is expressly incorporated herein by reference.
[0018] The present invention is based at least in part on data from
preclinical studies conducted in animal tumor models. The results
demonstrated that an anti-Fucosyl-GM1 antibody (e.g., BMS-986012)
is effective in treating a lung cancer.
I. Definitions
[0019] In order that the present disclosure may be more readily
understood, certain terms are first defined. As used in this
application, except as otherwise expressly provided herein, each of
the following terms shall have the meaning set forth below.
Additional definitions are set forth throughout the
application.
[0020] "Administering" refers to the physical introduction of a
composition comprising a therapeutic agent to a subject, using any
of the various methods and delivery systems known to those skilled
in the art. Preferred routes of administration for the
anti-Fucosyl-GM1 antibody include intravenous, intramuscular,
subcutaneous, intraperitoneal, spinal or other parenteral routes of
administration, for example, by injection or infusion. The phrase
"parenteral administration" as used herein means modes of
administration other than enteral and topical administration,
usually by injection, and includes, without limitation,
intravenous, intramuscular, intraarterial, intrathecal,
intralymphatic, intralesional, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticular, subcapsular,
subarachnoid, intraspinal, epidural and intrasternal injection and
infusion, as well as in vivo electroporation. The TKI is typically
administered via a non-parenteral route, preferably orally. Other
non-parenteral routes include a topical, epidermal or mucosal route
of administration, for example, intranasally, vaginally, rectally,
sublingually or topically. Administering can also be performed, for
example, once, a plurality of times, and/or over one or more
extended periods.
[0021] An "adverse event" (AE) as used herein is any unfavorable
and generally unintended or undesirable sign (including an abnormal
laboratory finding), symptom, or disease associated with the use of
a medical treatment. A medical treatment may have one or more
associated AEs and each AE may have the same or different level of
severity. Reference to methods capable of "altering adverse events"
means a treatment regime that decreases the incidence and/or
severity of one or more AEs associated with the use of a different
treatment regime.
[0022] An "antibody" (Ab) shall include, without limitation, a
glycoprotein immunoglobulin that binds specifically to an antigen
and comprises at least two heavy (H) chains and two light (L)
chains interconnected by disulfide bonds, or an antigen-binding
portion thereof. Each H chain comprises a heavy chain variable
region (abbreviated herein as V.sub.H) and a heavy chain constant
region. The heavy chain constant region comprises three constant
domains, C.sub.H1, C.sub.H2 and C.sub.H3. Each light chain
comprises a light chain variable region (abbreviated herein as
V.sub.L) and a light chain constant region. The light chain
constant region is comprises one constant domain, C.sub.L. The
V.sub.H and V.sub.L regions can be further subdivided into regions
of hypervariability, termed complementarity determining regions
(CDRs), interspersed with regions that are more conserved, termed
framework regions (FR). Each V.sub.H and V.sub.L comprises three
CDRs and four FRs, arranged from amino-terminus to carboxy-terminus
in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The
variable regions of the heavy and light chains contain a binding
domain that interacts with an antigen. The constant regions of the
Abs may mediate the binding of the immunoglobulin to host tissues
or factors, including various cells of the immune system (e.g.,
effector cells) and the first component (C1q) of the classical
complement system.
[0023] An immunoglobulin may derive from any of the commonly known
isotypes, including but not limited to IgA, secretory IgA, IgG and
IgM. IgG subclasses are also well known to those in the art and
include but are not limited to human IgG1, IgG2, IgG3 and IgG4.
"Isotype" refers to the Ab class or subclass (e.g., IgM or IgG1)
that is encoded by the heavy chain constant region genes. The term
"antibody" includes, by way of example, both naturally occurring
and non-naturally occurring Abs; monoclonal and polyclonal Abs;
chimeric and humanized Abs; human or nonhuman Abs; wholly synthetic
Abs; and single chain Abs. A nonhuman Ab may be humanized by
recombinant methods to reduce its immunogenicity in man. Where not
expressly stated, and unless the context indicates otherwise, the
term "antibody" also includes an antigen-binding fragment or an
antigen-binding portion of any of the aforementioned
immunoglobulins, and includes a monovalent and a divalent fragment
or portion, and a single chain Ab.
[0024] An "isolated antibody" refers to an Ab that is substantially
free of other Abs having different antigenic specificities (e.g.,
an isolated Ab that binds specifically to Fucosyl-GM1 is
substantially free of Abs that bind specifically to antigens other
than Fucosyl-GM1). Moreover, an isolated Ab may be substantially
free of other cellular material and/or chemicals.
[0025] The term "monoclonal antibody" ("MAb") refers to a
non-naturally occurring preparation of Ab molecules of single
molecular composition, i.e., Ab molecules whose primary sequences
are essentially identical, and which exhibits a single binding
specificity and affinity for a particular epitope. A MAb is an
example of an isolated Ab. MAbs may be produced by hybridoma,
recombinant, transgenic or other techniques known to those skilled
in the art.
[0026] A "human" antibody (HuMAb) refers to an Ab having variable
regions in which both the framework and CDR regions are derived
from human germline immunoglobulin sequences. Furthermore, if the
Ab contains a constant region, the constant region also is derived
from human germline immunoglobulin sequences. The human Abs of the
invention may include amino acid residues not encoded by human
germline immunoglobulin sequences (e.g., mutations introduced by
random or site-specific mutagenesis in vitro or by somatic mutation
in vivo). However, the term "human antibody", as used herein, is
not intended to include Abs in which CDR sequences derived from the
germline of another mammalian species, such as a mouse, have been
grafted onto human framework sequences. The terms "human" Abs and
"fully human" Abs and are used synonymously.
[0027] A "humanized antibody" refers to an Ab in which some, most
or all of the amino acids outside the CDR domains of a non-human Ab
are replaced with corresponding amino acids derived from human
immunoglobulins. In one embodiment of a humanized form of an Ab,
some, most or all of the amino acids outside the CDR domains have
been replaced with amino acids from human immunoglobulins, whereas
some, most or all amino acids within one or more CDR regions are
unchanged. Small additions, deletions, insertions, substitutions or
modifications of amino acids are permissible as long as they do not
abrogate the ability of the Ab to bind to a particular antigen. A
"humanized" Ab retains an antigenic specificity similar to that of
the original Ab.
[0028] A "chimeric antibody" refers to an Ab in which the variable
regions are derived from one species and the constant regions are
derived from another species, such as an Ab in which the variable
regions are derived from a mouse Ab and the constant regions are
derived from a human Ab.
[0029] An "anti-antigen" Ab refers to an Ab that binds specifically
to the antigen. For example, an anti-Fucosyl-GM1 Ab binds
specifically to Fucosyl-GM1.
[0030] An "antigen-binding portion" of an Ab (also called an
"antigen-binding fragment") refers to one or more fragments of an
Ab that retain the ability to bind specifically to the antigen
bound by the whole Ab.
[0031] A "cancer" refers a broad group of various diseases
characterized by the uncontrolled growth of abnormal cells in the
body. Unregulated cell division and growth divide and grow results
in the formation of malignant tumors that invade neighboring
tissues and may also metastasize to distant parts of the body
through the lymphatic system or bloodstream. The terms, "cancer",
"tumor", and "neoplasm", are used interchangeably herein.
[0032] A "subject" includes any human or nonhuman animal. The term
"nonhuman animal" includes, but is not limited to, vertebrates such
as nonhuman primates, sheep, dogs, and rodents such as mice, rats
and guinea pigs. In preferred embodiments, the subject is a human.
The terms, "subject" and "patient" are used interchangeably
herein.
[0033] A "therapeutically effective amount" or "therapeutically
effective dosage" of a drug or therapeutic agent is any amount of
the drug that, when used alone or in combination with another
therapeutic agent, protects a subject against the onset of a
disease or promotes disease regression evidenced by a decrease in
severity of disease symptoms, an increase in frequency and duration
of disease symptom-free periods, or a prevention of impairment or
disability due to the disease affliction. The ability of a
therapeutic agent to promote disease regression can be evaluated
using a variety of methods known to the skilled practitioner, such
as in human subjects during clinical trials, in animal model
systems predictive of efficacy in humans, or by assaying the
activity of the agent in in vitro assays.
[0034] By way of example, an "anti-cancer agent" promotes cancer
regression in a subject. In preferred embodiments, a
therapeutically effective amount of the drug promotes cancer
regression to the point of eliminating the cancer. "Promoting
cancer regression" means that administering an effective amount of
the drug, alone or in combination with an anti-neoplastic agent,
results in a reduction in tumor growth or size, necrosis of the
tumor, a decrease in severity of at least one disease symptom, an
increase in frequency and duration of disease symptom-free periods,
or a prevention of impairment or disability due to the disease
affliction. In addition, the terms "effective" and "effectiveness"
with regard to a treatment includes both pharmacological
effectiveness and physiological safety. Pharmacological
effectiveness refers to the ability of the drug to promote cancer
regression in the patient. Physiological safety refers to the level
of toxicity, or other adverse physiological effects at the
cellular, organ and/or organism level (adverse effects) resulting
from administration of the drug.
[0035] By way of example for the treatment of tumors, a
therapeutically effective amount of an anti-cancer agent preferably
inhibits cell growth or tumor growth by at least about 20%, more
preferably by at least about 40%, even more preferably by at least
about 60%, and still more preferably by at least about 80% relative
to untreated subjects. In other preferred embodiments of the
invention, tumor regression may be observed and continue for a
period of at least about 20 days, more preferably at least about 40
days, or even more preferably at least about 60 days.
Notwithstanding these ultimate measurements of therapeutic
effectiveness, evaluation of immunotherapeutic drugs must also make
allowance for "immune-related" response patterns.
[0036] A therapeutically effective amount of a drug includes a
"prophylactically effective amount", which is any amount of the
drug that, when administered alone or in combination with an
anti-neoplastic agent to a subject at risk of developing a cancer
(e.g., a subject having a pre-malignant condition) or of suffering
a recurrence of cancer, inhibits the development or recurrence of
the cancer. In preferred embodiments, the prophylactically
effective amount prevents the development or recurrence of the
cancer entirely. "Inhibiting" the development or recurrence of a
cancer means either lessening the likelihood of the cancer's
development or recurrence, or preventing the development or
recurrence of the cancer entirely.
[0037] The use of the alternative (e.g.,"or") should be understood
to mean either one, both, or any combination thereof of the
alternatives. As used herein, the indefinite articles "a" or "an"
should be understood to refer to "one or more" of any recited or
enumerated component.
[0038] The terms "about" or "comprising essentially of" refer to a
value or composition that is within an acceptable error range for
the particular value or composition as determined by one of
ordinary skill in the art, which will depend in part on how the
value or composition is measured or determined, i.e., the
limitations of the measurement system. For example, "about" or
"comprising essentially of" can mean within 1 or more than 1
standard deviation per the practice in the art. Alternatively,
"about" or "comprising essentially of" can mean a range of up to
20%. Furthermore, particularly with respect to biological systems
or processes, the terms can mean up to an order of magnitude or up
to 5-fold of a value. When particular values or compositions are
provided in the application and claims, unless otherwise stated,
the meaning of "about" or "comprising essentially of" should be
assumed to be within an acceptable error range for that particular
value or composition.
[0039] As described herein, any concentration range, percentage
range, ratio range or integer range is to be understood to include
the value of any integer within the recited range and, when
appropriate, fractions thereof (such as one-tenth and one-hundredth
of an integer), unless otherwise indicated.
[0040] Various aspects of the invention are described in further
detail in the following subsections.
II. Anti-Fucosyl-GM1 Antibodies
[0041] HuMAbs that bind specifically to Fucosyl-GM1 with high
affinity have been disclosed in U.S. Pat. No. 8,383,118 and WO
2007/067992 (e.g., human monoclonal antibodies 5B1, 5B1a, 7D4, 7E4,
13B8 and 18D5). Each of the HuMAbs disclosed in U.S. Pat. No.
8,383,118 has been demonstrated to exhibit one or more desirable
functional properties: (1) specifically binds to Fucosyl-GM1; (2)
binds to Fucosyl-GM1 with high affinity (for example, with a
K.sub.D of 1.times.10.sup.-7 M or less); (c) binds to the human
small cell lung cancer cell line DMS-79 (Human SCLC ATCC.RTM. No.
CRL-2049); and (d) inhibit growth of tumor cells in vitro or in
vivo. Preferably, the antibody binds to Fucosyl-GM1 with a K.sub.D
of 5.times.10.sup.-8 M or less, binds to Fucosyl-GM1 with a K.sub.D
of 1.times.10.sup.-8 M or less, binds to Fucosyl-GM1 with a K.sub.D
of 5.times.10.sup.-9 M or less, or binds to Fucosyl-GM1 with a
K.sub.D of between 1.times.10.sup.-8 M and 1.times.10.sup.-10 M or
less. Standard assays to evaluate the binding ability of the
antibodies toward Fucosyl-GM1 are known in the art, including, for
example, ELISAs, Western blots and RIAs. The binding kinetics
(e.g., binding affinity) of the antibodies also can be assessed by
standard assays known in the art, such as by ELISA, Scatchard and
BIACORE.RTM. analysis.
[0042] A preferred anti-Fucosyl-GM1 Ab is BMS-986012 (also referred
to as MDX-1110 or 7E4).
[0043] Anti-Fucosyl-GM1 Abs usable in the disclosed methods also
include isolated Abs that bind specifically to Fucosyl-GM1 and
cross-compete for binding to Fucosyl-GM1 with BMS-986012 (see,
e.g., U.S. Pat. No. 8,383,118; WO 2007/067992). The ability of Abs
to cross-compete for binding to an antigen indicates that these Abs
bind to the same epitope region of the antigen and sterically
hinder the binding of other cross-competing Abs to that particular
epitope region. These cross-competing Abs are expected to have
functional properties very similar those of BMS-986012 by virtue of
their binding to the same epitope region of Fucosyl-GM1.
Cross-competing Abs can be readily identified based on their
ability to cross-compete with BMS-986012 in standard Fucosyl-GM1
binding assays such as BIACORE.RTM. analysis, ELISA assays or flow
cytometry (see, e.g., WO 2013/173223).
[0044] For administration to human subjects, these Abs are
preferably chimeric Abs, or more preferably humanized or human Abs.
Such chimeric, humanized or human MAbs can be prepared and isolated
by methods well known in the art. Anti-Fucosyl-GM1 Abs usable in
the methods of the disclosed invention also include antigen-binding
portions of the above Abs. It has been amply demonstrated that the
antigen-binding function of an
[0045] Ab can be performed by fragments of a full-length Ab.
Examples of binding fragments encompassed within the term
"antigen-binding portion" of an Ab include (i) a Fab fragment, a
monovalent fragment consisting of the V.sub.L, V.sub.H, C.sub.L and
C.sub.H1 domains; (ii) a F(ab').sub.2 fragment, a bivalent fragment
comprising two Fab fragments linked by a disulfide bridge at the
hinge region; (iii) a Fd fragment consisting of the V.sub.H and
C.sub.H1 domains; and (iv) a Fv fragment consisting of the V.sub.L
and V.sub.H domains of a single arm of an Ab. Anti-Fucosyl-GM1
antibodies (or V.sub.H and/or V.sub.L domains derived therefrom)
suitable for use in the invention can be generated using methods
well known in the art.
[0046] An exemplary anti-Fucosyl-GM1 antibody is BMS-986012
comprising heavy and light chains comprising the sequences shown in
SEQ ID NOs: 3 and 4, respectively, or antigen binding fragments and
variants thereof.
[0047] In other embodiments, the antibody has heavy and light chain
CDRs or variable regions of BMS-986012. Accordingly, in one
embodiment, the antibody comprises CDR1, CDR2, and CDR3 domains of
the V.sub.L of BMS-986012 having the sequence set forth in SEQ ID
NO: 3, and CDR1, CDR2 and CDR3 domains of the V.sub.L of BMS-986012
having the sequence set forth in SEQ ID NO: 4. In another
embodiment, the antibody comprises the heavy chain CDR1, CDR2 and
CDR3 domains comprising the sequences set forth in SEQ ID NOs: 5,
6, and 7, respectively, and the light chain CDR1, CDR2 and CDR3
domains comprising the sequences set forth in SEQ ID NOs: 8, 9, and
10, respectively. In another embodiment, the antibody comprises
V.sub.H and/or V.sub.L regions comprising the amino acid sequences
set forth in SEQ ID NO: 3 and/or SEQ ID NO: 4, respectively. In
another embodiment, the antibody competes for binding with and/or
binds to the same epitope on Fucosyl-GM1 as the above-mentioned
antibodies. In another embodiment, the antibody has at least about
90% variable region amino acid sequence identity with the
above-mentioned antibodies (e.g., at least about 90%, 95% or 99%
variable region identity with SEQ ID NO: 3 or SEQ ID NO: 4).
III. Pharmaceutical Compositions
[0048] Therapeutic agents (e.g., anti-Fucosyl-GM1 antibodies) of
the present invention may be constituted in a composition, e.g., a
pharmaceutical composition containing and a pharmaceutically
acceptable carrier. As used herein, a "pharmaceutically acceptable
carrier" includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents, and the like that are physiologically compatible.
"Pharmaceutically acceptable" means approved by a government
regulatory agency or listed in the U.S. Pharmacopeia or another
generally recognized pharmacopeia for use in animals, particularly
in humans. The term "carrier" refers to a diluent, adjuvant,
excipient, or vehicle with which the compound is administered. Such
pharmaceutical carriers can be sterile liquids, such as water and
oils, including those of petroleum, animal, vegetable or synthetic
origin, such as peanut oil, soybean oil, mineral oil, sesame oil,
glycerol polyethylene glycol ricinoleate, and the like. Water or
aqueous solution saline and aqueous dextrose and glycerol solutions
may be employed as carriers, particularly for injectable solutions
(e.g., comprising an anti-Fucosyl-GM1 antibody). Preferably, the
carrier for a composition containing an Ab is suitable for
intravenous, intramuscular, subcutaneous, parenteral, spinal or
epidermal administration (e.g., by injection or infusion). A
pharmaceutical composition of the invention may include one or more
pharmaceutically acceptable salts, anti-oxidant, aqueous and
non-aqueous carriers, and/or adjuvants such as preservatives,
wetting agents, emulsifying agents and dispersing agents.
[0049] Liquid compositions for parenteral administration can be
formulated for administration by injection or continuous infusion.
Routes of administration by injection or infusion include
intravenous, intraperitoneal, intramuscular, intrathecal and
subcutaneous. In one embodiment, the anti-Fucosyl-GM1 antibody is
administered intravenously.
IV. Methods of Therapies
[0050] Provided herein are clinical methods for treating a lung
cancer (e.g., small cell lung cancer) in a subject (e.g., a human
subject), comprising administering to the subject a therapeutically
effective amount of an anti-Fucosyl-GM1 antibody or an
antigen-binding portion thereof. In one embodiment, the subject has
previously received an initial anti-cancer therapy. In another
embodiment, the lung cancer is an advanced, metastatic, relapsed,
and/or refractory lung cancer.
[0051] In a particular embodiment, the anti-Fucosyl-GM1 antibody is
BMS-986012. In another embodiment, dosage regimens are adjusted to
provide the optimum desired response (e.g., an effective
response).
[0052] In one embodiment, the dose of the anti-Fucosyl-GM1 antibody
is calculated per body weight, e.g., mg/kg body weight. In another
embodiment, the dose of the anti-Fucosyl-GM1 antibody is a
flat-fixed dose. In another embodiment, the dose of the
anti-Fucosyl-GM1 antibody is varied over time. For example, the
anti-Fucosyl-GM1 antibody may be initially administered at a high
dose and may be lowered over time. In another ebodiment, the
anti-Fucosyl-GM1 antibody is initially administered at a low dose
and increased over time.
[0053] In another embodiment, the amount of the antibody
administered is constant. In another embodiment, the amount of the
antibody administered varies with each dose. For example, the
maintenance (or follow-on) dose of the antibody can be higher or
the same as the loading dose that is first administered. In another
embodiment, the maintenance dose of the antibody can be lower or
the same as the loading dose.
[0054] In another embodiment, the antibody is administered as a
first line of treatment (e.g., the initial or first treatment). In
another embodiment, the antibody is administered as a second line
of treatment (e.g., after the initial or first treatment, including
after relapse and/or where the first treatment has failed).
[0055] Dosage and frequency vary depending on the half-life of the
Ab in the subject. In general, human Abs show the longest
half-life, followed by humanized Abs, chimeric Abs, and nonhuman
Abs. The dosage and frequency of administration can vary depending
on whether the treatment is prophylactic or therapeutic. In
prophylactic applications, a relatively low dosage is typically
administered at relatively infrequent intervals over a long period
of time. Some patients continue to receive treatment for the rest
of their lives. In therapeutic applications, a relatively high
dosage at relatively short intervals is sometimes required until
progression of the disease is reduced or terminated, and preferably
until the patient shows partial or complete amelioration of
symptoms of disease. Thereafter, the patient can be administered a
prophylactic regime.
[0056] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of the present invention may be varied
so as to obtain an amount of the active ingredient that is
effective to achieve the desired therapeutic response for a
particular patient, composition, and mode of administration,
without being unduly toxic to the patient. The selected dosage
level will depend upon a variety of pharmacokinetic factors
including the activity of the particular compositions of the
present invention employed, the route of administration, the time
of administration, the rate of excretion of the particular compound
being employed, the duration of the treatment, other drugs,
compounds and/or materials used in combination with the particular
compositions employed, the age, sex, weight, condition, general
health and prior medical history of the patient being treated, and
like factors well known in the medical arts. A composition of the
present invention can be administered via one or more routes of
administration using one or more of a variety of methods well known
in the art. As will be appreciated by the skilled artisan, the
route and/or mode of administration will vary depending upon the
desired results.
[0057] In certain embodiments, the anti-Fucosyl-GM1 antibody is
administered at a dose ranging from 10 to 2000 mg once every 1, 2,
3 or 4 weeks. For example, the antibody is administered at a dose
ranging from 20 to1000 mg once every 3 weeks. Optionally, the
method comprises at least one treatment cycle of three weeks. For
example, the method comprises at least four treatment cycles of
three weeks. To illustrate, the antibody is administered on Days 1,
22, 43, and 64.
[0058] In certain specific embodiments, the antibody is
administered according to at least one of the following dosing
regimens: (a) about 20 mg of the antibody every 3 weeks; (b) about
70 mg of the antibody every 3 weeks; (c) about 160 mg of the
antibody every 3 weeks; (d) about 400 mg of the antibody every 3
weeks; and (e) about 1000 mg of the antibody every 3 weeks.
Preferably, administration of the antibody induces a durable
clinical response in the subject. Optionally, administration of the
antibody is continued for as long as clinical benefit is observed
or until unmanageable toxicity or disease progression occurs. The
efficacy of the treatment methods provided herein can be assessed
using any suitable means. In one embodiment, the treatment produces
at least one therapeutic effect selected from the group consisting
of reduction in size of the cancer, reduction in number of
metastatic lesions over time, complete response, partial response,
and stable disease.
[0059] Patients treated according to the methods disclosed herein
preferably experience improvement in at least one sign of cancer.
In one embodiment, improvement is measured by a reduction in the
quantity and/or size of measurable tumor lesions. In another
embodiment, lesions can be measured on chest x-rays or CT or MRI
films. In another embodiment, cytology or histology can be used to
evaluate responsiveness to a therapy.
[0060] In one embodiment, the patient treated exhibits a complete
response (CR), a partial response (PR), or stable disease (SD). In
another embodiment, the patient treated experiences tumor shrinkage
and/or decrease in growth rate, i.e., suppression of tumor growth.
In another embodiment, unwanted cell proliferation is reduced or
inhibited. In yet another embodiment, one or more of the following
can occur: the number of cancer cells can be reduced; tumor size
can be reduced; cancer cell infiltration into peripheral organs can
be inhibited, retarded, slowed, or stopped; tumor metastasis can be
slowed or inhibited; tumor growth can be inhibited; recurrence of
tumor can be prevented or delayed; one or more of the symptoms
associated with cancer can be relieved to some extent.
V Kits and Unit Dosage Forms
[0061] Also provided herein are kits that include a pharmaceutical
composition containing an anti-Fucosyl-GM1 antibody (such as
BMS-986012), and a pharmaceutically acceptable carrier, in a
therapeutically effective amount adapted for use in the preceding
methods.
[0062] The kits optionally can also include instructions, e.g.,
comprising administration schedules, to allow a practitioner (e.g.,
a physician, nurse, or patient) to administer the composition
contained therein to administer the composition to a patient having
a cancer (e.g., a lung cancer). The kit can also include a
syringe.
[0063] Optionally, the kits include multiple packages of the
single-dose pharmaceutical compositions each containing an
effective amount of the antibody for a single administration in
accordance with the methods provided above. Instruments or devices
necessary for administering the pharmaceutical composition(s) also
may be included in the kits. For instance, a kit may provide one or
more pre-filled syringes containing an amount of the antibody.
[0064] In certain embodiments, the present invention provides a kit
for treating a subject afflicted with a lung cancer, the kit
comprising: (a) a dosage ranging from 10 to 2000 mg (e.g., at a
dosage from 20 to 1000 mg) of an anti-Fucosyl-GM1 antibody or an
antigen-binding portion thereof; and (b) instructions for using the
antibody in the method of the present invention. In certain
specific embodiments, the dosage of the antibody of the kit is
about 20 mg, 70 mg, 160 mg, 400 mg, or 1000 mg.
[0065] The following Examples are merely illustrative and should
not be construed as limiting the scope of this disclosure in any
way as many variations and equivalents will become apparent to
those skilled in the art upon reading the present disclosure.
[0066] The contents of all references, GENBANK.RTM. entries,
patents and published patent applications cited throughout this
application are expressly incorporated herein by reference.
EXAMPLE 1
Pre-Clinical In Vivo Efficacy Studies of BMS-986012
[0067] BMS-986012 is a first-in-class fully human immunoglobulin G
(IgG) monoclonal antibody (MAb) that specifically binds to the
Fucosyl-GM1 (Fuc-GM1) ganglioside. Immunohistochemical (IHC)
analysis of tumor samples with an anti-Fucosyl-GM1 MAb has
demonstrated antigen expression in a high percentage of SCLC cases
and little or no expression in normal tissues (Brezicka, T. et al.,
Lung Cancer, 28:29-36 (2000); Brezicka, F. T. et al., APMIS,
99:797-802 (1991); Zhang, S. et al., Int. J. Cancer, 73:42-49
(1997); Fredman, P. et al., Biochim. Biophys. Acta, 875:316-323
(1986); Brezicka, F. T. et al., Cancer Res., 49(5):1300-1305
(1989); Nilsson, O. et al., Cancer Res., 46:1403-1407 (1986)).
BMS-986012 exhibits high-affinity and dose-dependent saturable
binding to Fuc-GM1 and shows no detectable antigen-specific binding
to closely related molecule GM1. BMS-986012 was optimized to have
enhanced effector functions by elimination of the fucosylation on
the Fc domain. The absence of this fucosyl group in BMS-986012
(resulting from its expression in a cell line deficient in fucosyl
transferase) confers higher affinity for Fc receptors resulting in
enhanced antibody-dependent cellular cytotoxicity (ADCC).
Furthermore, the antibody was shown to mediate potent complement
dependent cytotoxicity (CDC) as well as antibody-dependent cellular
phagocytosis (ADCP). See, for example, WO 2007/067992, the content
of which is expressly incorporated herein by reference.
[0068] BMS-986012 in vivo efficacy was demonstrated in five of
seven mouse xenograft models tested. Table 1 below summarizes the
tumor growth inhibition data for the various xenograft studies
conducted.
TABLE-US-00001 TABLE 1 Efficacy of BMS-986012 on Fucosyl-GM1
Expressing Xenografts Model Efficacy (TGI) DMS79* 95% DMS53** 92%
H128** 20%{circumflex over ( )} H4IIE** 100% H740*** 39% H209***
None H187** 66% *3 mg/kg **10 mg/kg ***30 mg/kg TGI--mean tumor
growth inhibition when all mice were in study (between Day 15-69).
{circumflex over ( )}BMS-986012 induced a 20% TGI in the H128 model
- not statistically significant.
[0069] In one example, BMS-986012 induced dose-dependent tumor
growth inhibition on DMS79 xenografts while the IgG1 isotype
control had no anti-tumor efficacy (see FIG. 2). Maximal efficacy
appears to be reached at 0.3 mg/kg with near complete TGI of 95% to
98% at day 36. All doses of BMS-986012 were well-tolerated with no
body weight changes or signs of toxicity throughout the study. In a
second xenograft model (DMS53), BMS-986012 at 0.3, 10 and 30 mg/kg
resulted in statistically significant mean tumor growth inhibition
of 85%, 92% and 92%, respectively, compared with the PBS group and
cachexia was delayed in the BMS-986012 treated group. Body weight
loss correlated well with tumor burden.
[0070] Collectively, these data support that BMS-986012 has
significant anti-tumor activity in multiple tumor models.
EXAMPLE 2
Preclinical Pharmacology and Toxicity of BMS-986012
1. Pharmacology
[0071] BMS-986012 exhibits high affinity, dose dependent and
saturable binding to Fuc-GM1 and shows no detectable antigen
specific binding to a closely related molecule, GM1. Fuc-GM1 is a
chemically defined antigen that is identical in all species;
therefore BMS-986012 demonstrates high affinity binding to antigen
in all species including mouse, cynomolgus monkeys, and humans.
Immunohistochemical (IHC) analysis of tumor samples with the use of
a specific mouse monoclonal antibody to Fuc-GM1 has demonstrated
antigen expression in a high percentage of small cell lung cancer
(SCLC) cases.
[0072] BMS-986012 is expressed in a fucosyl transferase deficient
Chinese hamster ovary (CHO) cell line resulting in the production
of an antibody lacking fucose in its oligosaccharide chains. The
absence of fucose from the oligosaccharide of IgG1 conveys
increased antibody affinity for Fc receptor CD16 (Fc.gamma.RIIIa).
This Fc.gamma.R is expressed on NK cells and macrophages and is
responsible for ADCC. BMS-986012 demonstrated a 40.times. increase
in binding affinity for CD16 and a resulting 150.times. increase in
ADCC activity, compared with parental fucosylated monoclonal
antibody. In vitro, the antibody was shown to mediate potent
complement dependent cytotoxicity (CDC) as well as antibody
dependent cellular phagocytosis (ADCP). Robust in vivo tumor growth
inhibition was demonstrated in five out of seven tumor xenograft
models treated with BMS-986012 as a monotherapy.
2. Toxicity
[0073] The structure of Fuc-GM1 is homologous across all species,
and BMS-986012 demonstrates high affinity binding in all species
including mice, rats, cynomolgus monkeys, and humans. The
nonclinical safety of BMS-986012 was evaluated in a series of in
vitro tissue cross-reactivity studies and in vivo single- and
repeat-dose intravenous (IV) toxicity studies. The BMS-986012
binding profile was similar in human and cynomolgus monkey tissues
in the exploratory tissue cross reactivity study. In a single-dose
exploratory IV toxicity study in rats (0, 10, 40, or 150 mg/kg),
BMS-986012 was clinically tolerated at 10 mg/kg. The primary
BMS-986012-related finding at all doses was dose-related hemolytic
anemia and associated clinical toxicity resulting in humane
euthanasia of all rats at .gtoreq.40 mg/kg by Day 8. This hemolytic
anemia was considered to be pharmacologically mediated due to
expression of Fuc-GM1 on rat erythrocytes (Iwamori, M. et al.,
Glycoconjugate J., 26:467-476 (2009)). Fuc-GM1 is not expressed on
erythrocytes in other species including humans. Based on these
findings, which are not considered to be relevant to humans, the
rat was considered to be unacceptable for toxicological assessment
of BMS-986012. The mouse was selected as the rodent species for
further toxicology evaluation of BMS-986012.
[0074] In a pivotal 1-month IV toxicity study in mice (0, 10 or 150
mg/kg, QW, 5 doses), testicular toxicity characterized by decreased
testes weights with a microscopic correlate of bilateral germ cell
degeneration, retention of spermatids, and Sertoli cell vacuolation
was observed at both doses. The testicular toxicity observed in
mice was considered pharmacologically mediated and species specific
due to expression of Fuc-GM1 in mouse testes (Iwamori, M. et al.,
Biochem. J. 380:75-81 (2004); Sandhoff, R. et al., J. Biol. Chem.,
280:27310-27318 (2005)). Fuc-GM1 is not expressed in testes of
other species, including humans; therefore, testicular toxicity in
mice is considered not to be a concern in humans. The high dose of
150 mg/kg was clinically tolerated, whereas the low dose of 10
mg/kg resulted in mortality following at least 2 weekly doses that
was considered a consequence of an anti-drug antibody
(ADA)-mediated hypersensitivity. After a 6-week recovery period,
there was partial recovery of the BMS-986012-related testicular
changes at 10 mg/kg and progression of testicular toxicity at 150
mg/kg. A NOAEL was not established in this pivotal study due to
mortality at 10 mg/kg and testicular findings at 10 and 150 mg/kg.
The cause of the moribundity/mortality at 10 mg/kg was not apparent
from gross and microscopic examination of the tissues. However,
considering that these deaths occurred shortly after repeated IV
doses, the acute nature of the clinical signs, the presence of ADA
in this group (in satellite animals; ADAs were not analyzed in the
mice that were found dead or euthanized early), and the absence of
BMS-986012-related clinical signs or mortality at the high dose of
150 mg/kg, these deaths at 10 mg/kg likely were a consequence of an
ADA-mediated hypersensitivity reaction. A follow-up exploratory
immunotoxicity study in mice was conducted to determine the
potential contribution of ADA-mediated hypersensitivity as the
cause of the moribundity and mortality at 10 mg/kg. In this study
(0, 10, or 150 mg/kg, QW, up to 5 doses) in female mice,
BMS-986012-related moribundity and mortality again occurred only at
10 mg/kg with a strong correlation with high ADA levels. The
occurrence of BMS-986012-related effects (moribundity and
mortality) only at the low dose of 10 mg/kg, their onset after
multiple injections, and the strong correlation with high ADA
levels provide a weight of evidence of an ADA-mediated
hypersensitivity reaction (Michael, W. L. et al., Toxicol. Pathol.,
42:293-300 (2014)). This conclusion is further supported by the
lack of these findings in repeat dose studies (10 mg/kg, IP, up to
14 doses) in SCID mice, which cannot generate antibody
responses.
[0075] In an exploratory single-dose IV toxicity study in
cynomolgus monkeys (0, 10, 40, or 150 mg/kg), BMS-986012 was
clinically well tolerated at all doses with no adverse effects at
any dose. In the pivotal 1-month IV toxicity study in monkeys (0,
10 or 150 mg/kg, QW, 5 doses), BMS-986012 was clinically well
tolerated at all doses. Adverse findings were limited to the high
dose of 150 mg/kg and included decreases in circulating neutrophils
(0.02 to 0.54.times.) and platelets (0.32 to 0.50.times.) and
increased spleen size/weight and minimal subacute splenic
inflammation. Decreases in platelets and neutrophils were mostly
seen in animals with high ADA levels and was likely due to
Fc-mediated binding of BMS-986012/ADA immune complexes to these
cells resulting in clearance predominantly in the spleen. After a
2-month recovery period, all BMS-986012-related changes were
partially to fully reversible. The low dose of 10 mg/kg (mean
combined-sex AUC [0-168 h] 54,600 .mu.gh/mL) was considered a
NOAEL. The high dose of 150 mg/kg (mean combined-sex AUC [0-168 h]
733,000 .mu.gh/mL) was considered the HNSTD since it was clinically
tolerated and all adverse histopathology findings were
reversible.
[0076] No significant irritation or local tolerance issues were
observed at the injection sites following repeated IV dose
administration of BMS-986012 as a slow bolus injection at up to 150
mg/kg administered in the pivotal toxicity studies in mice and
cynomolgus monkeys. There were no BMS-986012-related
cardiovascular, respiratory, ophthalmologic, or neurological
effects at .ltoreq.150 mg/kg in monkeys (mean
C.sub.max.ltoreq.6,870 .mu.g/mL). In a GLP-compliant tissue
cross-reactivity study in normal human tissues, there was binding
of BMS-986012-FITC to neural elements (ganglion and satellite cells
and axons) that was anticipated based on literature reports of
Fuc-GM1 expression in peripheral nerves and dorsal root ganglia
(Yoshino, H. et al., J. Neurochem., 61(2):658-663 (1993); Kusunoki,
S. et al., Brain. Res., 494(2):391-395 (1989)). Expression of
Fuc-GM1 in healthy tissue is very limited; however, expression has
been associated with sensory nerves in monkeys and humans, making
peripheral neuropathy a potential target liability of BMS-986012.
Although Fuc-GM1 is reported to be expressed in neural tissues of
monkeys, BMS-986012 (150 mg/kg, Q2W, IV) when given alone to
monkeys for 3 months did not produce neurotoxicity or nerve
conduction deficits. Additionally, there was no
BMS-986012-FITC-specific staining in any of the adjacent-to-tumor
lung samples from smokers or nonsmokers, suggesting that smoking
did not induce the expression of Fuc-GM1 in normal human lung
tissue. Overall, the nonclinical toxicology assessment of
BMS-986012 has demonstrated an acceptable safety profile,
supporting clinical use in subjects with cancer.
EXAMPLE 3
[0077] A Phase 1/2 Multicenter Study of BMS-986012 in Subjects with
Relapsed/Refractory Small Cell Lung Cancer
1. Objectives
[0078] The primary objective of the study is to determine the
multidose safety, tolerability, dose limiting toxicities (DLTs),
and the maximally tolerated dose (MTD) of BMS-986012 administered
as monotherapy in subjects with relapsed or refractory SCLC.
[0079] Secondary objectives include characterizing the
pharmacokinetics (PK) of BMS-986012, investigating the preliminary
anti-tumor activity of BMS-986012 as measured by objective response
rate (ORR), duration of response, and progression-free survival
(PFS), characterizing the immunogenicity of BMS-986012, and
assessing the effect of BMS-986012 on the QT interval.
[0080] Additional exploratory objectives include exploring
associations between shed Fucosyl-GM1 (Fuc-GM1) at baseline and
anti-tumor activity, exploring associations between baseline
Fuc-GM1 positive circulating tumor cells (CTCs) and anti-tumor
activity, exploring associations of baseline NK-cell numbers,
phenotype (by FACS) and complement levels with pharmacodynamic
changes and anti-tumor activity, exploring Fuc-GM1-related
biomarkers such as, but not limited to, markers of neuroendocrine
differentiation as potential prognostic markers of anti-tumor
activity, exploring associations between Fc gamma receptor
(Fc.gamma.R) polymorphisms with anti-tumor activity, exploring the
PK-PD relationship(s) of BMS-986012, and assessing overall survival
(OS).
2. Study Design and Duration
[0081] This is an open-label ascending multiple dose study of
BMS-986012 administered once every 21 days (one cycle) as a single
agent and is conducted in two parts. Dose escalation (Part 1) is to
identify a potential MTD, or maximum administered dose (MAAD) if no
MTD is determined. In Part 2, additional subjects with SCLC are
enrolled at two doses at or below the MTD or MAAD to confirm safety
and evaluate efficacy at these doses. A study schematic is shown in
FIG. 3.
[0082] Subjects complete up to 4 periods in the study: Screening
(up to 28 days), Treatment (until meeting protocol-specified
discontinuation criteria), Clinical Follow-up (approximately 100
days), and Survival Follow-up (up to approximately 3 years).
Screening and Treatment periods are calculated relative to the
first dose of study drug, while follow-up periods are calculated
relative to the last dose of study drug.
[0083] Each treatment cycle consists of an IV infusion of
BMS-986012 every 21 days. Tumor response is assessed using Response
Evaluation Criteria for Solid Tumors version 1.1 (RECIST v1.1).
Subjects are allowed to continue treatment until documentation of
progressive disease or symptomatic deterioration, withdrawal of
consent, unacceptable adverse events, and/or meeting other
protocol-specified criteria for discontinuation.
[0084] After completion of the Clinical Follow-up period, subjects
enter the Survival follow-up period to collect data on survival
status. Subjects with stable disease, partial or complete response
at the end of the Clinical Follow-up period also undergo tumor
assessments every 3-4 months or as per institutional guidelines
until progression or starting a new anti-cancer therapy. Subjects
who have progressed in survival follow-up are allowed to receive
further anti-cancer therapy as required. The end of the study
occurs after the last treated subject has been followed for at
least 6 months from his/her last treatment date.
3. Dose Escalation (Part 1)
[0085] Enrollment in dose escalation and MTD selection adheres to a
modified Toxicity Probability Interval (mTPI) design (Ji, Y. et
al., J. Clin. Oncol., 31:1785-1791 (2013)), using cohorts of 3-6
subjects within a dose level, and allowing flexible decision-making
based on a minimum required cohort size. The design provides a
simple algorithm for decisions on escalation, expanding at the same
dose, and de-escalation, depending on the number of observed
toxicities after each dose cohort. The mTPI was selected over the
rule based 3+3 design as the mTPI is more likely to select the true
MTD and treat fewer subjects at suboptimal doses. The mTPI method
utilizes a target toxicity (DLT) rate and equivalence interval (EI)
to make decisions on escalation after each cohort and to estimate
the maximum tolerated dose (MTD). For this study the target DLT
rate is 25% and the EI is 23%-27%. A total of approximately 30
evaluable subjects are treated across the proposed dose levels as
shown in Table 2. Doses intermediate to those specified may be
evaluated if agreed upon by the Sponsor/Medical Monitor and
Investigators, provided the dose escalation increments are smaller
than those specified. No intra-subject dose escalation of
BMS-986012 is allowed at any dose level.
TABLE-US-00002 TABLE 2 Expected Dosages During Dose
Escalation.sup.a Dose Level Number BMS-986012 (mg IV Q3W) -1 21 1
70 2 160 3 400 4 1000 .sup.aInterim doses may be explored.
[0086] Dose escalation begins with Dose Level 1 and is guided by
the number of DLTs observed in 3-6 subjects treated initially per
dose cohort and evaluable for safety for at least 28 days;
additional subjects may be enrolled in cohorts of 3 to the same
dose level if needed. To minimize risks to subjects from
unanticipated acute toxicities, a waiting period of at least 5 days
occurs between administration of the first dose for the first,
second, and third subjects to create an observation period prior to
subsequent subject exposures. This waiting period is mandatory only
in Dose Level 1.
[0087] Decisions to escalate, add more subjects to the current
dose, deescalate, or deescalate and declare the current dose as
unacceptable (exceeding the MTD), are based on the rate of DLTs in
evaluable subjects within the 28-day DLT evaluation period (FIG.
4). DLT-evaluable subjects are defined as those receiving 2 doses
of study drug in the first 28 days of dosing. At least 3
DLT-evaluable subjects are required to enable a decision to
escalate, add more subjects to the current dose level, or
de-escalate.
[0088] FIG. 4 shows examples of scenarios guiding decision making
that may be encountered during dose escalation with respect to the
number of DLT evaluable subjects and the number of subjects with a
DLT. In addition to escalation or expansion decisions, dose
re-escalation is permitted after a decision to de-escalate is made,
except when a dose has been identified as exceeding the MTD.
Therefore, a dose level could be revisited multiple times under the
mTPI design.
[0089] At the end of the escalation phase, the cumulative number of
subjects who experience a DLT is used to estimate the MTD using
isotonic regression.
4. Dose Expansion (Part 2)
[0090] Doses selected for Part 2 do not exceed the MTD or MAAD, but
dose selection may incorporate assessment of other data including
toxicities and PK from Part 1. Part 2 evaluates toxicity and
preliminary efficacy of BMS-986012 as second-line monotherapy in
subjects who have relapsed following first-line chemotherapy as
follows: (Table 3) Cohort A: .ltoreq.3 m response duration
(refractory) at the MTD/MAAD identified in Part 1, Cohort B:
.ltoreq.3 m response duration (refractory) at a dose level below
the MTD/MAAD, Cohort C: >3 m response duration (sensitive) at
the MTD/MAAD, and Cohort D: >3 m response duration (sensitive)
at a dose level below the MTD/MAAD. The response duration
referenced above is relative to prior first-line therapy.
Approximately 22 refractory and 28 sensitive subjects are treated
per cohort. Enrollment is guided by the Simon 2-stage design
framework.
TABLE-US-00003 TABLE 3 Dose Expansion Cohorts Dose Expansion
Cohorts Maximum* Approximate Number of Cohort Definition Evaluable
Subjects A Relapsed/refractory.sup.a,b 22 B
Relapsed/refractory.sup.a,c 22 C Sensitive.sup.b,d 28 D
Sensitive.sup.c,d 28 .sup.a.ltoreq.3 mo response duration from most
recent cancer therapy .sup.bat MTD/MAAD .sup.cat a dose below
MTD/MAAD .sup.d>3 mo response duration from most recent cancer
therapy *Fewer subjects may be treated in a cohort with no evidence
of tumor activity, as guided by a Simon 2-Stage design.
[0091] Antitumor activity is assessed in approximately the first 9
or 10 evaluable subjects treated in each cohort, with the option to
stop enrolling in a cohort without an initial anti-tumor activity
signal. The number of subjects needed for the Stage 1 review is
guided by a Simon 2-Stage design, assuming a 25% desirable response
rate (vs. 10%) for refractory disease, and a 40% (vs. 25%) for
sensitive disease. In this setting, if none of the first 9
evaluable subjects in the refractory cohort or if fewer than 3
subjects of the first 10 evaluable subjects in a sensitive cohort
demonstrate clinical activity, enrollment in the cohort meeting
criteria may not continue. As the expected time of response
relative to dose initiation and the actual enrollment rate are
unknown, it is expected that during the efficacy evaluation of
subjects in Stage 1, more subjects may enroll and begin receiving
treatment than the minimum needed for the Stage 1 assessment.
Therefore, the above numbers are approximate and enrollment
continues during the evaluation of the interim data.
[0092] Evaluation of toxicity events in the cohort expansions is
performed throughout enrollment. If the aggregate rate of
toxicities meeting DLT criteria exceeds 27% across all subjects
treated in all cohorts, the findings are discussed by Investigators
and the BMS study team and further enrollment may be interrupted.
Depending on the nature and grade of toxicity and after assessing
the risk/benefit ratio, additional subjects may be treated at,
below, or intermediate to a dose level previously found to be safe
following discussion by the Sponsor/Medical Monitor and
Investigators based on the available data. Selection of a dose or
doses for these additional cohorts is guided by accumulated safety
and efficacy data; modeling may also be used to explore potential
dose-response relationships.
[0093] Following each treatment cycle, the decision to treat a
subject with additional cycles of study therapy is based on
assessment of toxicity and tumor assessment. Subjects are generally
allowed to continue study therapy until the subject meets criteria
for discontinuation of study therapy as outlined in Section
3.5.
[0094] Available fresh tumor biopsies (either in the form of
snap-frozen or otherwise unfixed tissue or a new tumor tissue if
the biopsy procedure may be performed with minimal risk to the
subject as judged by the Investigator), are evaluated for
Fucosyl-GM1 expression and Fucosyl-GM1-related biomarkers including
but not limited to neuroendocrine biomarkers. If available,
archived biopsies are evaluated for Fucosyl-GM1-related biomarkers
including but not limited to neuroendocrine markers.
5. Dose-Limiting Toxicity
[0095] For the purpose of guiding dose escalation, DLTs are defined
based on incidence, intensity, and duration of adverse events (AEs)
for which no clear alternative cause is identified. Subjects must
receive 2 doses of study drug during the 28-day DLT evaluation
period to be considered evaluable for dose escalation decisions.
Adverse events are graded according to the National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events
version 4.03 (CTCAE v4.03). For the purpose of subject management,
any AE that meets DLT criteria, regardless of the cycle in which it
occurs, leads to dose interruption. AEs occurring after the 28 day
DLT period are considered for the purposes of defining the MTD upon
agreement between the Sponsor/Medical Monitor and Investigators, if
they are determined to have no clear alternative cause and are not
related to disease progression.
[0096] Dose escalation is based on the number of DLTs experienced,
as guided by the escalation design algorithm (FIG. 4) and agreed
upon by the Medical Monitor and the Investigators. No intra-subject
dose escalation is allowed. Subjects who withdraw from the study
during the DLT evaluation interval for reasons other than a DLT may
be replaced at the same dose level.
6. Duration of Study
[0097] The screening period lasts up to 28 days. Subjects receive
BMS-986012 every 21 days until meeting protocol-specified criteria
for discontinuation. The clinical follow-up period is approximately
100 days following the last treatment with BMS-986012, including
subjects discontinuing the study for disease progression unless
subjects have withdrawn consent or initiated additional anti-cancer
therapy. After completing the clinical follow-up period, subjects
continue to be followed for overall survival up to 3 years from end
of treatment. Subjects with stable disease, partial or complete
response at EOT also undergo tumor assessment every 3-4 months or
as per institutional guidelines until progression or starting a new
anti-cancer therapy. The end of the study occurs after the last
treated subject has been followed for at least 6 months from
his/her last treatment date.
7. Number of Subjects
[0098] During dose escalation (Part 1) up to approximately 30
evaluable subjects are expected to be treated. Although the exact
number per dose level depends on the number of observed toxicities,
approximately 3-9 subjects are expected to be enrolled in each dose
level during dose escalation. In Part 2, approximately 100
evaluable subjects are treated. Approximately 170 subjects are
estimated to be enrolled in this study, including subjects screened
but not meeting eligibility criteria and subjects treated but
requiring replacement.
[0099] Additional subjects may be enrolled in escalation or
expansion cohorts, if needed to maintain a sufficient number of
subjects evaluable for safety or antitumor activity.
8. Study Population
[0100] Men and women at least 18 years of age with histological or
cytological confirmed SCLC and ECOG Performance Status 0-1 and
meeting all other eligibility criteria may participate in the
study. Subjects must not have symptomatic or untreated CNS
metastases. All SCLC subjects must have relapsed after or be deemed
refractory to first-line standard of care chemotherapy. Subjects
who have received second- or third-line therapy are eligible for
the dose escalation phase (Phase 1) but not the dose expansion
phase (Phase 2).
[0101] Women of childbearing potential must not be nursing or
pregnant. All women must have a negative pregnancy test within 24
hours prior to dosing with study medication.
9. Study Drug
[0102] Study Drug for CA001030 can be found in Table 4 below.
TABLE-US-00004 TABLE 4 Medication Potency Investigational Product
(IP)/Non-IP BMS-986012 120 mg/vial IP (Solution for Injection)
.sup. (30 mg/mL)
10. Study Assessments
[0103] Safety Outcome Measures: Adverse events are assessed during
treatment and until 100 days after the last treatment. Serious
adverse events are collected from the time a subject signs informed
consent and for approximately 100 days after the last treatment.
Adverse events are coded using the most current version of MedDRA
and reviewed for potential significance and importance. Adverse
events are evaluated according to the NCI CTCAE Version 4.03.
Subjects should be followed until adverse events have recovered to
grade .ltoreq.1 or baseline, or are deemed irreversible by the
Investigator. Safety assessments are based on medical review of
adverse event reports and the results of vital sign measurements,
ECGs, physical examinations, clinical laboratory tests, and
available radiographic tests. Serial ECGs are collected from a
minimum of 50 subjects across doses with most subjects at the MTD
(MAAD) to measure QT, other ECG intervals and heart rate to explore
the potential effect of study drug on QTc.
[0104] Pharmacokinetic Measures: Pharmacokinetic parameters
(C.sub.max, T.sub.max, C.sub.tau, AUC.sub.0-t, AUC.sub.tau) are
derived from serum concentration versus time data by compartment
model independent data analysis methods. Efficacy Measures: Disease
assessments using computed tomography (CT) and/or magnetic
resonance imaging (MRI) as appropriate, are performed at baseline
and every 6 weeks (every 2 cycles) until disease progression or as
planned per protocol. Tumor responses are determined by the
Investigator for subjects with adequate data as defined by RECIST
v1.1. At the Sponsor's discretion, de-identified scans and
measurements may be collected and reviewed by independent
radiologists using RECIST v1.1 criteria at a later date, or at any
time during the study.
[0105] Immunogenicity Measures: Serum samples to evaluate
development of positive anti-drug antibody (ADA) response to
BMS-986012 are collected at specified time points.
[0106] Exploratory Biomarker Measures: Baseline subject level total
shed Fuc-GM1, CTC counts and Fuc-GM1 positive CTC counts are
measured. Post-treatment shed Fuc-GM1 may be tested with
technologies including but not limited to ELISA. Measurement of
baseline and post-treatment subject level NK and
monocyte/macrophage counts, NK immunophenotyping and complement
assessment is also planned. Germline DNA assessments are conducted
from whole blood collected on Day 1 to assess inherited genotypes
of the IgG-binding Fc.gamma.R family. Genomic DNA is isolated and
specific single nucleotide polymorphisms (SNPs) of Fc.gamma.RIIIa
(158V/F), Fc.gamma.RIIa (131H/R), and Fc.gamma.RIIIb (NA1/NA2) are
evaluated by PCR to determine potential associations with
anti-tumor activity. All available fresh biopsies are evaluated for
Fuc-GM1 expression and Fuc-GM1 related biomarkers including but not
limited to neuroendocrine biomarkers. Any available archived FFPE
biopsies are evaluated for Fuc-GM1 related biomarkers including but
not limited to neuroendocrine biomarkers.
11. Statistical Considerations
[0107] Sample Size:
[0108] For Dose Escalation, a total of approximately 30 evaluable
subjects are expected to be treated during dose escalation. The
exact number depends on the number of observed DLTs, and is guided
by the escalation design, which selects a MTD with a 25% target DLT
rate, while also taking into account the number of early
dropouts.
[0109] For Dose Expansion, the total sample size per each expansion
cohort (approximately n=22 for refractory and approximately n=28
for sensitive) is planned to provide reasonably reliable estimates
for ORR, and adequate false positive and false negative rates. In
addition, as guided by a Simon 2-stage design, a minimum of 9 and
10 evaluable subjects per refractory or sensitive cohort are
expected to be treated in Stage 1 to allow for an initial
evaluation of efficacy. The probability of early stopping is 39%
(minimax design) with 9 subjects in a refractory cohort and 53%
(optimal design) with 10 subjects in a sensitive cohort. The number
of subjects receiving treatment at the time of the Stage 1 efficacy
evaluation is approximate and may exceed the minimum number of
evaluable subjects required for response assessment due to unknown
time expected for a potential response, and the unknown true
recruitment rate. In the refractory tumor expansion cohort of
approximately 22 subjects with an assumed 25% true ORR, there is an
84% chance of observing at least 4 responses, a 68% chance of
observing at least 5 responses, and a 16% chance of observing 3 or
fewer responses (false negative rate). If the true ORR is 10%
instead of 25%, then there is a 17% and 6% chance respectively that
there are at least 4 or at least 5 responses in 22 subjects (false
positive rate). In addition, if 4 or 5 responses are observed,
assuming a 25% ORR, then the lower limit of the 80% CI for the ORR
is 8.2% or 12% respectively.
[0110] For the sensitive tumor expansion cohort of 28 subjects and
an assumed 40% true ORR, there is an 85% chance of observing at
least 9 responses, a 74% chance of observing at least 10 responses,
and a 15% chance of observing 8 or fewer responses (false negative
rate). If the true ORR is 25% instead of 40%, then there is 25% and
14% chance respectively that there are at least 9 or at least 10
responses in 28 subjects (false positive rate). In addition, if 8
or 9 responses are observed, assuming a 40% ORR, then the lower
limit of the 80% CI for the ORR is 17% or 20% respectively. The
confidence interval calculations are based on the Clopper-Pearson
method for exact confidence intervals.
12. Endpoints
[0111] The primary endpoint of this phase 1/2 study is safety as
measured by the rate of adverse events (AEs), serious adverse
events (SAEs), discontinuations due to AEs, deaths, and clinically
significant laboratory abnormalities. Safety is evaluated once a
subject signs informed consent through Clinical Follow-up.
[0112] Secondary endpoints include efficacy, pharmacokinetics,
immunogenicity, and exploratory biomarkers.
[0113] (1) Efficacy: The objective response rate (ORR), duration of
response, and progression free survival (PFS) are assessed based on
RECIST v1.1 criteria. In addition, PFS rates at pre-specified
timepoints, e.g., 24, 36 weeks are assessed. Individual best
overall response (BOR) is a subject level endpoint. The above is
determined based on tumor measurements occurring every 6 weeks
during the Treatment Period, and at approximately the 100-day
Clinical Follow-up visit, according to institutional practice.
Subjects not progressing at discontinuation of study treatment
undergo tumor assessments every 3-4 months or as per institutional
practice until the date of the first objective documentation of
tumor progression or death due to any cause.
[0114] (2) Pharmacokinetics: C.sub.max, T.sub.max, C.sub.tau,
AUC.sub.0-t, AUC.sub.tau
[0115] (3) Immunogenicity: Occurrence of specific anti-drug
antibodies (ADA) to BMS-986012. Samples are collected at multiple
time points.
[0116] (4) Exploratory Biomarkers: Shed Fuc-GM1, Fuc-GM1 positive
CTCs, NK and monocyte/macrophage counts, NK immunophenotyping,
complement levels and Fc.gamma.R polymorphisms. If available,
Fuc-GM1 IHC of fresh biopsies and evaluation of Fuc-GM1 related
biomarkers of archived FFPE biopsies including but not limited to
neuroendocrine biomarkers.
13. Analyses
[0117] Safety Analysis: All recorded adverse events are listed and
tabulated by system organ class, preferred term and treatment.
Vital signs and clinical laboratory test results are listed and
summarized by treatment. Any significant physical examination
findings, and clinical laboratory results are listed. ECG readings
are evaluated by the Investigator and abnormalities, if present,
are listed. For subjects with serial ECG measurements, changes in
the QTcF (.DELTA.QTcF), ECG intervals QRS, and PR, and in heart
rate (.DELTA.HR) are tabulated by dose and study day. Scatter plots
of heart rate, .DELTA.HR, QTcF, and .DELTA.QTcF, vs time-matched
BMS-986012 concentrations are provided. A concentration-response
effect of BMS-986012 on QTcF may be assessed by a linear mixed
effects regression model for .DELTA.QTcF on plasma concentrations,
stratified by study day, as well as pooled across days.
[0118] Efficacy Analyses: Individual best overall response (BOR),
duration of response and PFS are listed using RECIST v1.1 criteria.
BOR outcomes are tabulated by disease type and dose. The objective
response rate (ORR) and PFS rates (e.g., at 24 weeks) and the
confidence interval are provided by dose and overall for each
disease type. The duration of response and PFS are estimated by
Kaplan-Meier (K-M) methodology by disease type. Presentations of
efficacy include subjects in cohort expansion and subjects in dose
escalation matching the dose and disease type (refractory or
sensitive). Individual changes in the tumor burden over time are
presented graphically by dose within a disease type. Overall
survival is also assessed as part of exploratory efficacy analysis,
by Kaplan-Meier plots and medians and OS rates, at specified
timepoints, e.g., at 6 or 12 months.
[0119] Pharmacokinetic Analyses: PK parameters are summarized by
dose. Descriptive statistics are presented for C.sub.max,
C.sub.tau, AUC.sub.0-t, and AUC.sub.tau. Medians and ranges are
presented for T.sub.max.
[0120] Immunogenicity Analyses: All available immunogenicity data
are listed, with flags for subjects with at least one positive
anti-drug antibody (ADA) at any time point. The frequency of
subjects with at least one positive ADA assessment, and frequency
of subjects who develop ADA after a negative baseline assessment
are provided. Associations of immunogenicity measures with PK
and/or select AE may be explored.
[0121] Exploratory Biomarker Analyses: Analysis to explore
associations of baseline markers with efficacy measures is
performed (e.g., graphically), for baseline value of shed Fuc-GM1
antigen levels, Fuc-GM1 positive CTCs, or relative Fuc-GM1
expression, and Fc.gamma.R polymorphisms, and further assessed as
needed by methods such as logistic regression. The pharmacodynamic
effect on markers is assessed by summary statistics and plots over
time by dose to explore patterns of change over time, and how the
patterns differ among dose levels.
[0122] Interim Analysis: Data emerging from this study may be
needed for timely decisions about adjustments to procedures in
subsequent parts of the study. Therefore, data may be reviewed
prior to the final lock of the study database. Additional interim
analyses may also be performed for administrative purposes or
publications. Analyses may only consist of listings, summaries, and
graphs of the available data. No formal inferences requiring any
adjustment to statistical significance level are performed.
Efficacy analyses based on interim data may use response evaluable
or all treated populations depending on the purpose of the
analysis.
Sequence CWU 1
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attagtcgta gtggtcgtga catatactac 180gcagactctg tgaagggccg
attcaccatc tccagagaca atgccaagaa ctcactgtat 240ctgcaaatga
acagcctgag agacgaggac acggctgtgt attactgtgc gggaactgta
300acgacatact actacgactt cggtatggac gtctggggcc aagggaccac
ggtcaccgtc 360tcctca 3662321DNAHomo sapiens 2gacatccaga tgacccagtc
tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca
gggtattagc agctggttag cctggtatca gcagaaacca 120gagaaagccc
ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca
180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag
cctgcagcct 240gaagattttg caacttatta ctgccaacag tataatagtt
accctcccac tttcggcgga 300gggaccaagg tggagatcaa a 3213122PRTHomo
sapiens 3Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro
Gly Glu1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe
Ser Arg Tyr 20 25 30Lys Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
Leu Glu Trp Val 35 40 45Ser Tyr Ile Ser Arg Ser Gly Arg Asp Ile Tyr
Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Asp
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Gly Thr Val Thr Thr Tyr
Tyr Tyr Asp Phe Gly Met Asp Val Trp 100 105 110Gly Gln Gly Thr Thr
Val Thr Val Ser Ser 115 1204107PRTHomo sapiens 4Asp Ile Gln Met Thr
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30Leu Ala Trp
Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile 35 40 45Tyr Ala
Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75
80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Pro
85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
10555PRTHomo sapiens 5Arg Tyr Lys Met Asn1 5617PRTHomo sapiens 6Tyr
Ile Ser Arg Ser Gly Arg Asp Ile Tyr Tyr Ala Asp Ser Val Lys1 5 10
15Gly713PRTHomo sapiens 7Thr Val Thr Thr Tyr Tyr Tyr Asp Phe Gly
Met Asp Val1 5 10811PRTHomo sapiens 8Arg Ala Ser Gln Gly Ile Ser
Ser Trp Leu Ala1 5 1097PRTHomo sapiens 9Ala Ala Ser Ser Leu Gln
Ser1 5109PRTHomo sapiens 10Gln Gln Tyr Asn Ser Tyr Pro Pro Thr1
5
* * * * *