U.S. patent application number 16/605226 was filed with the patent office on 2020-02-20 for endocrine therapy and abemaciclib combination for the adjuvant treatment of node-positive, early stage, hormone receptor-positiv.
The applicant listed for this patent is Eli Lilly and Company. Invention is credited to Ian Charles SMITH.
Application Number | 20200054634 16/605226 |
Document ID | / |
Family ID | 62117181 |
Filed Date | 2020-02-20 |
United States Patent
Application |
20200054634 |
Kind Code |
A1 |
SMITH; Ian Charles |
February 20, 2020 |
ENDOCRINE THERAPY AND ABEMACICLIB COMBINATION FOR THE ADJUVANT
TREATMENT OF NODE-POSITIVE, EARLY STAGE, HORMONE RECEPTOR-POSITIVE,
HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2-NEGATIVE BREAST CANCER
Abstract
The present invention discloses an adjuvant treatment of
node-positive, early stage, hormone receptor-positive (HR+), human
epidermal growth factor receptor 2-negative (HER2-) breast cancer
comprising administering an effective amount of an endocrine
therapy in combination with an effective amount of abemaciclib or a
pharmaceutically acceptable salt thereof.
Inventors: |
SMITH; Ian Charles; (Carmel,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Eli Lilly and Company |
Indianapolis |
IN |
US |
|
|
Family ID: |
62117181 |
Appl. No.: |
16/605226 |
Filed: |
April 25, 2018 |
PCT Filed: |
April 25, 2018 |
PCT NO: |
PCT/US2018/029289 |
371 Date: |
October 15, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62500068 |
May 2, 2017 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4196 20130101;
A61K 31/5685 20130101; A61P 35/04 20180101; A61K 31/506 20130101;
A61K 31/138 20130101; A61K 31/506 20130101; A61K 2300/00 20130101;
A61K 31/138 20130101; A61K 2300/00 20130101; A61K 31/4196 20130101;
A61K 2300/00 20130101; A61K 31/5685 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61K 31/138 20060101 A61K031/138; A61K 31/4196
20060101 A61K031/4196; A61K 31/5685 20060101 A61K031/5685; A61P
35/04 20060101 A61P035/04 |
Claims
1. A method of providing adjuvant treatment to a patient with a
prior diagnosis of node-positive, early stage, HR+, HER2- breast
cancer which has been resected comprising administering an
effective amount of an endocrine therapy in combination with an
effective amount of abemaciclib or a pharmaceutically acceptable
salt thereof for a time period sufficient to increase distant
relapse-free survival.
2. The method according to claim 1 wherein the endocrine therapy is
tamoxifen or a pharmaceutically acceptable salt thereof.
3. The method according to claim 1 wherein the endocrine therapy is
letrozole.
4. The method according to claim 1 wherein the endocrine therapy is
anastrozole.
5. The method according to claim 1 wherein the endocrine therapy is
exemestane.
6. The method according to claim 1 wherein the abemaciclib or the
salt thereof is administered at 150 mg twice daily.
7. The method according to claim 1 wherein the abemaciclib or the
salt thereof is administered at 100 mg twice daily.
8-16. (canceled)
17. The method according to claim 2 wherein the abemaciclib or the
salt thereof is administered at 150 mg twice daily.
18. The method according to claim 2 wherein the abemaciclib or the
salt thereof is administered at 100 mg twice daily.
19. The method according to claim 3 wherein the abemaciclib or the
salt thereof is administered at 150 mg twice daily.
20. The method according to claim 3 wherein the abemaciclib or the
salt thereof is administered at 100 mg twice daily.
21. The method according to claim 4 wherein the abemaciclib or the
salt thereof is administered at 150 mg twice daily.
22. The method according to claim 4 wherein the abemaciclib or the
salt thereof is administered at 100 mg twice daily.
23. The method according to claim 5 wherein the abemaciclib or the
salt thereof is administered at 150 mg twice daily.
24. The method according to claim 5 wherein the abemaciclib or the
salt thereof is administered at 100 mg twice daily.
Description
[0001] The present invention relates to the field of adjuvant
treatment of node-positive, early stage, hormone receptor-positive
(HR+), human epidermal growth factor receptor 2-negative (HER2-)
breast cancer.
[0002] The currently approved standards of care offered to patients
with node-positive, early stage, hormone receptor-positive (HR+),
human epidermal growth factor receptor 2-negative (HER2-) breast
cancer are adjuvant cytotoxic chemotherapy and endocrine therapy.
Unfortunately, with current standard of care adjuvant therapy,
approximately 30% of women with hormone receptor positive (HR+)
breast cancer initially diagnosed with early stage disease
experience distant relapse with metastases. Consequently, there is
a critical need for more optimal adjuvant therapy in patients with
early HR+ breast cancer who have a high likelihood of distant
recurrence.
[0003] According to one aspect of the present invention, there is
presented a method of providing adjuvant treatment to a patient
with a prior diagnosis of node-positive, early stage, HR+, HER2-
breast cancer which has been resected comprising administering an
effective amount of an endocrine therapy in combination with an
effective amount of abemaciclib or a pharmaceutically acceptable
salt thereof for a time period sufficient to increase distant
relapse-free survival. Preferably the endocrine therapy is
tamoxifen or a pharmaceutically acceptable salt thereof. Preferable
the endocrine therapy is letrozole. Preferably the endocrine
therapy is anastrozole. Preferably the endocrine therapy is
exemestane.
[0004] According to another aspect of the present invention, there
is presented a combination comprising therapeutically effective
amounts of abemaciclib, or a pharmaceutically acceptable salt
thereof, and an endocrine therapy for simultaneous, separate, or
sequential use in providing adjuvant treatment to a patient with a
prior diagnosis of node-positive, early stage, HR+, HER2- breast
cancer which has been resected, wherein administration of the
abemaciclib or the salt thereof and the endocrine therapy is for a
time period sufficient to increase distant relapse-free survival.
Preferably the endocrine therapy is tamoxifen or a pharmaceutically
acceptable salt thereof. Preferable the endocrine therapy is
letrozole. Preferably the endocrine therapy is anastrozole.
Preferably the endocrine therapy is exemestane.
[0005] According to another aspect of the present invention, there
is presented a therapeutically effective amount of abemaciclib, or
a pharmaceutically acceptable salt thereof, for use in
simultaneous, separate, or sequential combination with a
therapeutically effective amount of an endocrine therapy in
providing adjuvant treatment to a patient with a prior diagnosis of
node-positive, early stage, HR+, HER2- breast cancer which has been
resected, wherein administration of the abemaciclib or the salt
thereof and the endocrine therapy is for a time period sufficient
to increase distant relapse-free survival. According to another
aspect of the present invention, there is presented a
therapeutically effective amount of an endocrine therapy for use in
simultaneous, separate, or sequential combination with a
therapeutically effective amount of abemaciclib, or a
pharmaceutically acceptable salt thereof, in providing adjuvant
treatment to a patient with a prior diagnosis of node-positive,
early stage, HR+, HER2- breast cancer which has been resected,
wherein administration of the abemaciclib or the salt thereof and
the endocrine therapy is for a time period sufficient to increase
distant relapse-free survival. Preferably the endocrine therapy is
tamoxifen or a pharmaceutically acceptable salt thereof. Preferable
the endocrine therapy is letrozole. Preferably the endocrine
therapy is anastrozole. Preferably the endocrine therapy is
exemestane.
[0006] According to another aspect of the present invention, there
is also presented the use of abemaciclib, or a pharmaceutically
salt thereof, in the manufacture of a medicament for providing
adjuvant treatment of node-positive, early stage, HR+, HER2- breast
cancer which has been resected wherein the abemaciclib, or the salt
thereof, is to be administered in simultaneous, separate, or
sequential combination with an endocrine therapy for a time period
sufficient to increase distant relapse-free survival. Preferably
the endocrine therapy is tamoxifen or a pharmaceutically acceptable
salt thereof. Preferable the endocrine therapy is letrozole.
Preferably the endocrine therapy is anastrozole. Preferably the
endocrine therapy is exemestane.
[0007] According to another aspect of the present invention, there
is also presented the use of an endocrine therapy in the
manufacture of a medicament for providing adjuvant treatment of
node-positive, early stage, HR+, HER2- breast cancer which has been
resected wherein the endocrine therapy is to be administered in
simultaneous, separate, or sequential combination with abemaciclib,
or a pharmaceutically salt thereof, for a time period sufficient to
increase distant relapse-free survival. Preferably the endocrine
therapy is tamoxifen or a pharmaceutically acceptable salt thereof.
Preferable the endocrine therapy is letrozole. Preferably the
endocrine therapy is anastrozole. Preferably the endocrine therapy
is exemestane.
[0008] For all of the preceding aspects, the following are
preferred dosing. Preferably, abemaciclib, or the pharmaceutically
salt thereof, is administered at a dose of 50 mg to 200 mg twice a
day. Also preferably, abemaciclib, or the pharmaceutically salt
thereof, is administered at a dose of 100 mg to 150 mg twice a day.
More preferably, abemaciclib, or the pharmaceutically salt thereof,
is administered at a dose of 200 mg twice a day. More preferably,
abemaciclib, or the pharmaceutically salt thereof, is administered
at a dose of 150 mg twice a day in a 28-day cycle. More preferably,
abemaciclib, or the pharmaceutically salt thereof, is administered
at a dose of 100 mg twice a day in a 28-day cycle. More preferably,
abemaciclib, or the pharmaceutically salt thereof, is administered
at a dose of 50 mg twice a day in a 28-day cycle. Preferably,
abemaciclib is administered orally. More preferably, abemaciclib is
administered by capsule. Also more preferably, abemaciclib is
administered by tablet.
[0009] Preferably, an endocrine therapy is administered as
described on the approved label of the particular endocrine
therapy. For example, tamoxifen or a pharmaceutically acceptable
salt thereof may be administered at 20-40 mg/day. For doses over 20
mg, the dose should be administered in a divided dose of morning
and evening. Doses are preferably oral. For example, anastrazole
may be administered at 1 mg/day. Doses are preferably oral. For
example, letrozole may be administered at 2.5 mg/day. Doses are
preferably oral. For example, exemestane may be administered at 25
mg/day. Doses are preferably oral.
[0010] Preferably, tamoxifen or a pharmaceutically acceptable salt
thereof is administered at 20-40 mg/day and abemaciclib or a
pharmaceutically acceptable salt thereof is administered at 200 mg
twice daily. Preferably, tamoxifen or a pharmaceutically acceptable
salt thereof is administered at 20-40 mg/day and abemaciclib or a
pharmaceutically acceptable salt thereof is administered at 150 mg
twice daily. Preferably, tamoxifen or a pharmaceutically acceptable
salt thereof is administered at 20-40 mg/day and abemaciclib or a
pharmaceutically acceptable salt thereof is administered at 100 mg
twice daily. For doses of tamoxifen or a salt thereof over 20 mg,
the dose should be administered in a divided dose of morning and
evening. Doses are preferably oral for both tamoxifen or the salt
thereof and abemaciclib or the salt thereof.
[0011] Preferably, anastrazole is administered at 1 mg/day and
abemaciclib or a pharmaceutically acceptable salt thereof is
administered at 200 mg twice daily. Preferably, anastrazole is
administered at 1 mg/day and abemaciclib or a pharmaceutically
acceptable salt thereof is administered at 150 mg twice daily.
Preferably, anastrazole is administered at 1 mg/day and abemaciclib
or a pharmaceutically acceptable salt thereof is administered at
100 mg twice daily. Doses are preferably oral for both anastrazole
and abemaciclib or the salt thereof.
[0012] Preferably, letrozole is administered at 2.5 mg/day and
abemaciclib or a pharmaceutically acceptable salt thereof is
administered at 200 mg twice daily. Preferably, letrozole is
administered at 2.5 mg/day and abemaciclib or a pharmaceutically
acceptable salt thereof is administered at 150 mg twice daily.
Preferably, letrozole is administered at 2.5 mg/day and abemaciclib
or a pharmaceutically acceptable salt thereof is administered at
100 mg twice daily. Doses are preferably oral for both anastrazole
and abemaciclib or the salt thereof.
[0013] Preferably, exemestane is administered at 25 mg/day and
abemaciclib or a pharmaceutically acceptable salt thereof is
administered at 200 mg twice daily. Preferably, exemestane is
administered at 25 mg/day and abemaciclib or a pharmaceutically
acceptable salt thereof is administered at 150 mg twice daily.
Preferably, exemestane is administered at 25 mg/day and abemaciclib
or a pharmaceutically acceptable salt thereof is administered at
100 mg twice daily. Doses are preferably oral for both anastrazole
and abemaciclib or the salt thereof.
[0014] As used herein, the term "patient" refers to a human.
[0015] As used herein, the terms "cancer" and "cancerous" refer to
or describe the physiological condition in patients that is
typically characterized by unregulated cell proliferation.
[0016] As used herein, the term "effective amount" refers to the
amount or dose of abemaciclib, or a pharmaceutically acceptable
salt thereof, and the amount or dose of an endocrine therapy which
provides an effective response in the patient under diagnosis or
treatment.
[0017] As used herein, the term "effective response" of a patient
or a patient's "responsiveness" to treatment with a combination of
agents refers to the clinical or therapeutic benefit imparted to a
patient upon administration of abemaciclib, or a pharmaceutically
acceptable salt thereof, and an endocrine therapy.
[0018] As used herein, the term "in combination with" refers to the
administration of abemaciclib, or a pharmaceutically acceptable
salt thereof, and an endocrine therapy either simultaneously or
sequentially in any order, such as for example, at repeated
intervals as during a standard course of treatment for a single
cycle or more than one cycle, such that one agent can be
administered prior to, at the same time, or subsequent to the
administration of the other agent, or any combination thereof.
[0019] Abemaciclib (LY2835219),
[5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-i-
sopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine, is
a CDK inhibitor that targets the CDK4 and CDK6 cell cycle pathway,
with antineoplastic activities. Abemaciclib, including salt forms,
and methods of making and using this compound including for the
treatment of cancer, in particular, breast cancer are disclosed in
WO2010/075074. Abemaciclib has the following structure:
##STR00001##
[0020] Abemaciclib showed antitumor activity within multiple
preclinical pharmacology models and an acceptable toxicity profile
in nonclinical species. Abemaciclib has been shown to significantly
inhibit tumor growth in multiple murine xenograft models for human
cancer, including breast cancer. Growth inhibition in vitro across
a diverse panel of 46 breast cancer cell lines, representing the
known molecular subgroups of breast cancer, indicates that
sensitivity to CDK4 and CDK6 inhibition is greater in ER+ breast
cancers with luminal histology.
[0021] Continuously dosed abemaciclib has demonstrated robust
single-agent clinical activity in both the JPBA Phase 1b study with
a response rate of 33.3% across dose levels and the MONARCH 1 Phase
2 study with a response rate of 19.7% (at 200-mg dose twice daily),
in patients with heavily pretreated HR+ metastatic breast cancer
that is refractory to endocrine therapy (Patnaik et al. 2016;
Dickler et al. 2016).
[0022] When combined with standard endocrine therapies (for
example, tamoxifen, letrozole, anastrozole, exemestane),
abemaciclib demonstrated early evidence of antitumor activity
against HR+ mBC (objective response rate: 10% to 40%; disease
control rate: 60% to 87.5%) and was tolerable in the ongoing JPBH
Phase 1b study (Beeram et al. 2016). In JPBH, the most common
adverse events (AEs) experienced by patients receiving abemaciclib
plus endocrine therapy included fatigue, nausea, diarrhea,
leukopenia, lymphopenia, neutropenia, and anemia, which are
predominantly of low-grade severity and appear to be
dose-dependent.
[0023] In early neoadjuvant breast cancer setting, the ongoing
neoMONARCH Phase 2 open-label, randomized study (I3Y-MC-JPBY)
showed an acceptable safety profile for abemaciclib (150 mg twice
daily) as monotherapy and in combination with anastrozole, with
reduction of breast cancer tumor cell proliferation marker (Ki67
index) to a significantly greater extent than anastrozole alone
(Hurvitz et al. 2016).
[0024] As used herein, the term "endocrine therapy" means tamoxifen
or a pharmaceutically acceptable salt thereof, anastrozole,
letrozole, or exemestane.
[0025] Tamoxifen is a selective estrogen receptor modulators (SERM)
with tissue-specific activities for the treatment and prevention of
estrogen receptor positive breast cancer. Tamoxifen acts as an
anti-estrogen (inhibiting agent) in the mammary tissue, but as an
estrogen (stimulating agent) in cholesterol metabolism, bone
density, and cell proliferation in the endometrium. Tamoxifen has
the following structure:
##STR00002##
[0026] Anastrozole is a drug indicated in the treatment of breast
cancer in postmenopausal women. It is used both in adjuvant therapy
(i.e. following surgery) and in metastatic breast cancer. It
decreases the amount of estrogens that the body makes. Anastrozole
belongs in the class of drugs known as aromatase inhibitors. It
inhibits the enzyme aromatase, which is responsible for converting
androgens (produced by women in the adrenal glands) to estrogens.
Anastrozole has the following structure:
##STR00003##
[0027] Letrozole is an oral non-steroidal aromatase inhibitor that
has been introduced for the adjuvant treatment of
hormonally-responsive breast cancer. Letrozole has the following
structure:
##STR00004##
[0028] Exemestane is an oral steroidal aromatase inhibitor used in
the adjuvant treatment of hormonally-responsive (also called
hormone-receptor-positive, estrogen-responsive) breast cancer in
postmenopausal women. It acts as a false substrate for the
aromatase enzyme, and is processed to an intermediate that binds
irreversibly to the active site of the enzyme causing its
inactivation. Exemestane has the following structure:
##STR00005##
[0029] As used herein, the term "resection" means surgical removal
of malignant tissue characteristic of breast cancer from a patient.
According to one embodiment, resection means removal of malignant
tissue such that the presence of remaining malignant tissue within
said patient is undetectable with available methods. According to
another embodiment of the invention resection means removal of
breast cancer such that the presence of remaining breast cancer
with said patient is undetectable.
[0030] As used herein, the term "distant relapse-free survival"
means the time from starting treatment of the combination of
abemaciclib or the salt thereof and the endocrine therapy to
disease recurrence, distant metastases, or death from any
cause.
[0031] As used herein, the term "early stage" means cancers that
may have spread to nearby lymph nodes but not to distant parts of
the body.
[0032] As used herein, the term "treating", "treatment", or
adjuvant treatment" means the administration of a drug or drugs to
a patient after surgical resection of one or more cancerous tumors,
where all detectable and resectable disease (for example, cancer)
has been removed from the patient, but where there remains a
statistical risk of relapse due to occult disease, for the purpose
of diminishing the likelihood or the severity of reoccurance of the
disease, or to delay the onset of the biological manifestation of
the reoccurance of the disease.
[0033] "Ki67 antigen" or simply "Ki67" (also known as antigen
identified by monoclonal antibody Ki-67) means a nuclear protein
encoded by the MKI67 gene that is expressed in all phases of the
cell cycle other than the GO phase and has been reported as an
independent prognostic factor in early breast cancer (Dowsett et
al. 2011). In HR+ breast cancer, patients with high levels of Ki67
have been shown to have higher disease recurrence rates while
receiving adjuvant endocrine therapy following surgery. In the BIG
1-98 study (Viale et al. 2008), patients receiving letrozole with
HR+ early breast cancer involving their axillary lymph nodes and
low (<11%) Ki67 levels at baseline had a 4-year disease-free
survival of 93% compared to 85% for patients with higher Ki67
values (>11%). Currently, there is no consensus as to the
precise baseline level of Ki67 that would differentiate a patient
for being of higher or lower risk of disease recurrence whilst on
adjuvant endocrine therapy. However, the majority of the panel of
the St Gallen International Expert Consensus on the Primary Therapy
of Early Breast Cancer 2015 was prepared to accept a threshold
value of Ki67 within the range of 20% to 29% (Vasconcelos et al.
2016) as indicative of high-risk group appropriate to receive
adjuvant chemotherapy.
EXAMPLE 1
A Randomized, Open-Label, Phase 3 Study of Abemaciclib Combined
with Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant
Endocrine Therapy Alone in Patients with High Risk, Node Positive,
Early Stage, Hormone Receptor Positive, Human Epidermal Receptor 2
Negative, Breast Cancer
[0034] The primary objective of this study is to evaluate the
efficacy, in terms of invasive disease-free survival (IDFS), as
defined by the STEEP System, for patients with HR+, HER2- early
stage breast cancer for abemaciclib 150 mg twice daily plus
adjuvant endocrine therapy versus adjuvant endocrine therapy
alone.
The secondary objectives of this study is to [0035] evaluate the
efficacy, in terms of IDFS, for patients with HR+, HER2- early
stage breast cancer with Ki67 index.gtoreq.20% (both Cohort 1 and
Cohort 2 by central lab); [0036] evaluate the efficacy of
abemaciclib plus adjuvant endocrine therapy versus adjuvant
endocrine therapy alone in terms of distant relapse-free survival
(DRFS) and overall survival (OS); [0037] assess the safety profile
of abemaciclib plus adjuvant endocrine therapy compared to adjuvant
endocrine therapy alone; [0038] evaluate the relationship between
abemaciclib exposure and clinical (efficacy and safety) outcomes;
[0039] evaluate abemaciclib plus adjuvant endocrine therapy, versus
adjuvant endocrine therapy alone, in terms of general oncology and
breast cancer self-reported health-related quality of life
(Functional Assessment of Cancer Therapy [FACT]-Breast 37-item
questionnaire), endocrine therapy-specific symptoms (Functional
Assessment of Cancer Therapy-Endocrine Symptoms (Version 4)
[FACT-ES] 19-item subscale and 2 Functional Assessment of Chronic
Illness Therapy Item Library [FACIT] (Version 2) sourced items of
cognitive symptoms and 3 FACIT-sourced items for bladder symptoms),
and fatigue experienced during abemaciclib and/or endocrine therapy
(FACIT-Fatigue 13-item subscale); and [0040] evaluate health status
to inform decision modeling for health economic evaluation using
the EuroQol five-dimension five-level questionnaire.
[0041] The study will screen approximately 4200 patients, and
approximately 3580 patients will be enrolled and subdivided into 2
cohorts: those eligible based on nodal status, tumor size, or grade
regardless of Ki67 status, Cohort 1, and those with at least 1
positive node and eligible exclusively based on a Ki67 status,
Cohort 2 (that is, those patients not eligible based on tumor size
or grade). Cohort 1 will enroll approximately 3080 patients and
Cohort 2 will enroll approximately 500 patients.
[0042] Patients in both treatment arms will receive standard
adjuvant endocrine therapy of physician's choice (such as tamoxifen
or an aromatase inhibitor, with or without ovarian function
suppression per standard practice). Patients in both arms may have
started standard adjuvant endocrine therapy within 8 weeks prior to
randomization, and the same or another endocrine therapy will be
continued during the course of the study and in the absence of
disease recurrence. Consistent with standard guidelines, aromatase
inhibitor should be at least part of endocrine therapy for
postmenopausal patients. Adjuvant treatment with fulvestrant is not
allowed at any time during the study. Randomization must occur no
more than 12 weeks after completion of last non-endocrine therapy
(surgery, or chemotherapy or radiotherapy). Patients randomized to
the experimental arm will receive abemaciclib orally at 150 mg
twice daily for up to 2 years or until evidence of disease
recurrence or other discontinuation criteria are met, whichever
occurs first. Endocrine therapy will be taken as prescribed during
the on-study treatment period. (Years 1 and 2). In Year 3 and
beyond, standard adjuvant endocrine therapy will continue to
complete at least 5 years per investigator's discretion as part of
standard of care.
* * * * *