U.S. patent application number 15/663082 was filed with the patent office on 2018-02-01 for methods of treating prostate cancer.
The applicant listed for this patent is Janssen Pharmaceutica NV. Invention is credited to Marco Gottardis, Rebecca Hawkins, Linda A Snyder, Douglas H. Yamada.
Application Number | 20180028521 15/663082 |
Document ID | / |
Family ID | 59649991 |
Filed Date | 2018-02-01 |
United States Patent
Application |
20180028521 |
Kind Code |
A1 |
Gottardis; Marco ; et
al. |
February 1, 2018 |
Methods of Treating Prostate Cancer
Abstract
Disclosed are methods of treating prostate cancer by
administering niraparib to a human in need thereof.
Inventors: |
Gottardis; Marco;
(Princeton, NJ) ; Hawkins; Rebecca; (Harleysville,
PA) ; Snyder; Linda A; (Pottstown, PA) ;
Yamada; Douglas H.; (Philadelphia, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutica NV |
Beerse |
|
BE |
|
|
Family ID: |
59649991 |
Appl. No.: |
15/663082 |
Filed: |
July 28, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62368466 |
Jul 29, 2016 |
|
|
|
62369239 |
Aug 1, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/454 20130101;
A61P 13/08 20180101; A61K 9/0053 20130101; A61P 35/04 20180101;
A61P 35/00 20180101 |
International
Class: |
A61K 31/454 20060101
A61K031/454; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method of treating prostate cancer in a human in need of such
treatment comprising administering to the human a safe and
effective amount of niraparib.
2. A method of claim 1, wherein the prostate cancer is
castration-resistant prostate cancer or metastatic
castration-resistant prostate cancer.
3. A method of claim 2, wherein the prostate cancer is antiandrogen
resistant.
4. A method as in claim 3, wherein the human is carrying at least
one DNA repair anomaly selected from the group consisting of
BRCA-1, BRCA-2, FANCA, PALB2, CHEK2, HDAC2, and ATM.
5. A method of claim 4, where in the DNA repair anomaly is BRCA-1
or BRCA-2.
6. A method of claim 5, wherein the prostate cancer is
castration-resistant prostate cancer.
7. A method of claim 5, wherein the prostate cancer is metastatic
castration-resistant prostate cancer.
8. A method of claim 6, wherein niraparib is administered in an
amount of from about 30 mg/day to about 400 mg/day.
9. A method of claim 8, wherein the amount of niraparib
administered is about 300 mg/day.
10. A method of claim 9, wherein niraparib is administered as once
daily oral administration in three 100 mg oral dosage forms.
11. A method of treating castration and anti androgen resistant
prostate cancer in a human comprising administering three 100 mg
oral dosage forms niraparib once daily to the human.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Not applicable.
FIELD OF THE INVENTION
[0002] The present invention relates to the treatment of metastatic
hormone-naive prostate cancer in a human by administering a safe
and/or an effective amount of niraparib to such human.
BACKGROUND OF THE INVENTION
[0003] Prostate cancer is the most common non-cutaneous malignancy
in men and the second leading cause of death in men from cancer in
the western world. Prostate cancer results from the uncontrolled
growth of abnormal cells in the prostate gland. Once a prostate
cancer tumor develops, androgens, such as testosterone, promote
prostate cancer tumor growth. At its early stages, localized
prostate cancer is often treated with local therapy including, for
example, surgical removal of the prostate gland and radiotherapy.
However, when local therapy fails to cure prostate cancer, as it
does in up to a third of men, the disease progresses into incurable
metastatic disease (i.e., disease in which the cancer has spread
from one part of the body to other parts).
[0004] Treatment of metastatic prostate cancer Androgen deprivation
therapy ("ADT") or androgen suppression therapy is performed to
reduce the testicular production of testosterone. ADT includes
surgical castration (orchiectomy) or the use of luteinizing
hormone-releasing hormone ("LHRH") antagonists or agonists.
Examples of LHRH antagonists include degarelix. Examples of LHRH
agonists include goserelin acetate, histrelin acetate, leuprolide
acetate, and triptorelin palmoate. Abiraterone acetate is a prodrug
of abiraterone, inhibits 17.alpha., hydroxylase/C17, 20-lyase
(cytochrome P4.50c17 [CYP17]), a key enzyme in androgen
biosynthesis. Abiraterone acetate in combination with prednisone
has been approved for the treatment of men with metastatic
castration-resistant prostate cancer ("mCRPC") who have received
prior chemotherapy containing docetaxel. The efficacy and safety of
abiraterone acetate (1,000 mg daily tablet dose) and prednisone (5
mg twice daily) therapy in patients with mCRPC is established by
the results of COU-AA-301 and COU-AA-302, both Phase 3,
multinational, randomized, double-blind, placebo-controlled
studies. Study COU-AA-301 was the first Phase 3 study to
demonstrate that further lowering testosterone concentrations below
that achieved with androgen deprivation therapy ("ADT") using CYP17
inhibition with abiraterone acetate improves survival in patients
with mCRPC. COU-AA-302 demonstrated significantly improved overall
survival ("OS") and radiographic progression-free survival ("rPFS")
in chemotherapy-naive patients with mCRPC treated with abiraterone
acetate plus prednisone compared with placebo plus prednisone. What
is needed are data to determine whether abiraterone acetate in
combination with low-dose prednisone and ADT is superior to ADT
alone in improving rPFS and OS in subjects with mHNPC with
high-risk prognostic factors.
[0005] Thus, the treatment of prostate cancer, including castrate
resistant prostate cancer and metastatic castrate resistant
prostate cancer, by way of PARP inhibition with niraparib in mCRPC
patients, including those with DNA-repair anomalies. This treatment
may follow chemotherapy or may be a chemo-naive subject. This
treatment may follow AR-targeted agents, enzalutamide, apalutamide,
and bicalutamide. Therefore, niraparib may present another
treatment option.
SUMMARY OF THE INVENTION
[0006] The present invention is directed to a method for treating
prostate cancer in a human in need of such treatment comprising,
consisting of, and/or consisting essentially of administering to
the human a therapeutically effective amount of niraparib.
[0007] In an embodiment, the present invention is directed to a
method of treating prostate cancer in a human in need of such
treatment comprising, consisting of, and/or consisting essentially
of administering to the human a therapeutically effective amount of
niraparib, wherein the prostate cancer is castration-resistant
prostate cancer ("CRPC"), metastatic castration-resistant prostate
cancer, and/or antiandrogen-resistant prostate cancer.
[0008] In another embodiment, the present invention is directed a
method for treating prostate cancer in a human in need of such
treatment comprising, consisting of and/or consisting essentially
of administering niraparib to a human, wherein the human is
carrying at least one DNA repair anomaly selected from the group
consisting of BRCA-1, BRCA-2, FANCA, PALB2, CHEK2, BRIP1, HDAC2,
and ATM.
[0009] In another embodiment, the present invention is directed a
method for treating prostate cancer in a human in need of such
treatment comprising, consisting of and/or consisting essentially
of administering niraparib to a human, wherein the human is
carrying at least one DNA repair anomaly that is either BRCA-1 or
BRCA-2.
[0010] In another embodiment, the present invention is directed to
a method of treating prostate cancer in a human in need of such
treatment comprising, consisting of, and/or consisting essentially
of administering to the human niraparib in an amount of,
preferably, from about 30 mg/day to about 400 mg/day, more
preferably 300 mg/day, and most preferably once daily oral
administration in three 100 mg oral dosage forms.
[0011] In another embodiment, the present invention is directed to
a composition comprising niraparib for the treatment of prostate
cancer, antiandrogen resistant prostate cancer,
castration-resistant prostate cancer, and metastatic
castration-resistant prostate cancer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1. Illustrates that niraparib inhibits the growth of
human prostate tumor cell lines in vitro.
[0013] FIG. 2. Illustrates that niraparib suppresses PAR formation
in two human prostate tumor cell lines in vitro.
[0014] FIG. 3. Illustrates that niraparib treatment induces
increased .gamma.-H2AX in 22RV1 cells in a dose-dependent manner,
as measured by flow cytometry.
[0015] FIG. 4. Illustrates that niraparib induces .gamma.-H2 AX in
22RV1, LNCaP AR-TB, and C4-2B cells in vitro.
[0016] FIG. 5. Illustrates that niraparib treatment inhibits growth
of C4-2B-luc prostate tumors in NSG male mice.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The term "subject" refers to a mammal, most preferably a
human, who has been or is the object of treatment, observation or
experiment.
[0018] The term "treatment" refers to the treatment of a subject
afflicted with a pathological condition and refers to an effect
that alleviates the condition by killing the cancerous cells, but
also to an effect that results in the inhibition of the progress of
the condition, and includes a reduction in the rate of progress, a
halt in the rate of progress, amelioration of the condition, and
cure of the condition. Treatment as a prophylactic measure (i.e.,
prophylaxis) is also included.
[0019] The term "therapeutically effective amount" refers to an
amount of niraparib that elicits the biological or medicinal
response in a tissue system that is being sought by a researcher,
veterinarian, medical doctor or other clinician, which includes
alleviation or partial alleviation of the symptoms of the disease,
syndrome, condition, or disorder being treated.
[0020] The term "safe and effective amount" refers to an amount of
niraparib that elicits the prevention or amelioration of disease
progression and unacceptable toxicity in the human.
[0021] The term "composition" refers to a pharmaceutical product
that includes the specified ingredients sometimes in
therapeutically effective amounts, as well as any product that
results, directly, or indirectly, from combinations of the
specified ingredients in the specified amounts.
[0022] The term "pharmaceutically acceptable" as used herein
pertains to compound, materials, compositions and/or dosage forms
that are, within the scope of sound medical judgement, suitable for
use in contact with the tissues of a human without excessive
toxicity, irritations, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk ratio.
Each carrier, excipient, etc. must all be "acceptable" in the sense
of being compatible with the other ingredients of the
formulation.
[0023] The term "androgen receptor" as used herein is intended to
include the wild-type androgen receptor as well as
androgen-resistant ARs and/or AR mutants associated with
castration-resistant prostate cancer.
[0024] As used herein, the term "antiandrogen" refers to a group of
hormone receptor antagonist compounds that is capable of preventing
or inhibiting the biologic effects of androgens on normally
responsive tissues in the body. In some embodiments, an
anti-androgen is a small molecule. Antiandrogens include
enzalutamide, apalutamide, and abiraterone acetate.
[0025] As used herein, the term "first-generation anti-androgen"
refers to an agent that exhibits antagonist activity against a
wild-type AR polypeptide. However, first-generation anti-androgens
differ from second-generation anti-androgens in that
first-generation anti-androgens can potentially act as agonists in
CRPC. Exemplary first-generation anti-androgens include, but are
not limited to, flutamide, nilutamide and bicalutamide.
[0026] As used herein, the term "second-generation anti-androgen"
refers to an agent that exhibits fill antagonist activity against a
wild-type AR polypeptide. Second-generation anti-androgens differ
from first-generation anti-androgens in that second-generation
anti-androgens act as full antagonists in cells expressing elevated
levels of AR, such as for example, in CRTC. Exemplary
second-generation anti-androgens include
4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-d-
iazaspiro[3,4]oct-5-yl]-2-fluoro-N methylbenzamide (also known as
ARN-509; CAS No. 956104-40-8);
4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimida-
zolidin-1-yl)-2-fluoro-N-methylbenzamide (also known as MDV3100 or
enzalutamide; CAS No: 915087-33-1) and RD162 (CAS No. 915087-27-3).
In some embodiments, a second-generation anti-androgen binds to an
AR polypeptide at or near the ligand binding site of the AR
polypeptide.
[0027] As used herein, the term "third-generation anti-androgen"
refers to an agent that exhibits full antagonist activity against a
wild-type AR polypeptide and against mutant forms of the AR
polypeptide, with mutations arising in the ligand binding domain
(LBD) of the AR polypeptide as set forth below. Third-generation
anti-androgens retain the differentiation from first-generation
anti-androgens in that third-generation anti-androgens act as full
antagonists in cells expressing elevated levels of AR, such as for
example, in CRPC.
[0028] As used herein, the term "mutant" refers to an altered (as
compared with a reference) nucleic acid or polypeptide, or to a
cell or organism containing or expressing such altered nucleic acid
or polypeptide.
[0029] As used herein, unless otherwise noted, the term "affect" or
"affected" (when referring to a disease, syndrome, condition or
disorder that is affected by antagonism of AR) includes a reduction
in the frequency and/or severity of one or more symptoms or
manifestations of said disease, syndrome, condition or disorder;
and/or include the prevention of the development of one or more
symptoms or manifestations of said disease, syndrome, condition or
disorder or the development of the disease, condition, syndrome or
disorder.
[0030] Embodiments of the present invention include prodrugs of
niraparib. In general, such prodrugs will be functional derivatives
of the compounds that are readily convertible in vivo into the
required compound. Thus, in the methods of treating or preventing
embodiments of the present invention, the term "administering"
encompasses the treatment or prevention of the various diseases,
conditions, syndromes and disorders described with the compound
specifically disclosed or with a compound that may not be
specifically disclosed, but which converts to the specified
compound in vivo after administration to a patient. Conventional
procedures for the selection and preparation of suitable prodrug
derivatives are described, for example, in "Design of Prodrugs",
ed. H. Bundgaard, Elsevier, 1985.
[0031] Androgen Receptor (AR)
[0032] Androgens bind to a specific receptor, the androgen receptor
(AR), inside the cells of target tissues. The AR is expressed in
numerous tissues of the body and is the receptor through which the
physiological as well as the pathophysiological effects of
endogenous androgen ligands, such as testosterone (T) and
dihydrotestosterone (DHT), are expressed. Structurally, the AR is
composed of three main functional domains: the ligand binding
domain (LBD), the DNA-binding domain, and amino-terminal domain. A
compound that binds to the AR and mimics the effects of an
endogenous AR ligand is referred to as an AR agonist, whereas a
compound that inhibits the effects of an endogenous AR ligand is
termed an AR antagonist. Binding of androgen to the receptor
activates it and causes it to bind to DNA binding sites adjacent to
target genes. From there it interacts with coactivator proteins and
basic transcription factors to regulate the expression of the gene.
Thus, via its receptor, androgens cause changes in gene expression
in cells. These changes ultimately have consequences on the
metabolic output, differentiation or proliferation of the cell that
are visible in the physiology of the target tissue. In the
prostate, androgens stimulate the growth of prostate tissue and
prostate cancer cells by binding to the AR that is present within
the cytoplasm of androgen sensitive tissue.
[0033] Compounds that selectively modulate AR are of clinical
importance in the treatment of or prevention of a variety of
diseases, conditions, and cancers, including, but not limited to,
prostate cancer, benign prostatic hyperplasia, hirsutism in women,
alopecia, anorexia nervosa, breast cancer, acne, musculoskeletal
conditions, such as bone disease, hematopoietic conditions,
neuromuscular disease, rheumatological disease, cancer, AIDS,
cachexia, for hormone replacement therapy (HRT), employed in male
contraception, for male performance enhancement, for male
reproductive conditions, and primary or secondary male
hypogonadism.
[0034] Castration Resistant Prostate Cancer
[0035] Agents that block the action (antiandrogens) of endogenous
hormones (e.g., testosterone) are highly effective and routinely
used for the treatment of prostate cancer (androgen ablation
therapy). While initially effective at suppressing tumor growth,
these androgen ablation therapies eventually fail in almost all
cases, leading CRPC. Most, but not all, prostate cancer cells
initially respond to androgen withdrawal therapy. However, with
time, surviving populations of prostate cancer cells emerge because
they have responded to the selective pressure created by androgen
ablation therapy and are now refractory to it. Not only is the
primary cancer refractory to available therapies, but cancer cells
may also break away from the primary tumor and travel in the
bloodstream, spreading the disease to distant sites (especially
bone). This is known as metastatic castration resistant prostate
cancer ("mCRPC"). Among other effects, this causes significant pain
and further bone fragility in the subject.
[0036] In some embodiments, the subject's prostate cancer is
resistant to or non-responsive to antiandrogen treatment,
including, but not limited to, enzalutamide, apalutamide and
abiraterone acetate ("antiandrogen resistance").
[0037] The preparation of niraparib,
2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide, may be
found in U.S. Pat. No. 8,071,623, issued on Dec. 6, 2011 and
entitled Amide Substituted Indazoles as Poly(ADP-Ribose)Polymerase
(PARP) inhibitors, which claims the benefit of U.S. provisional
patent application No. 60/921,310, filed on Feb. 16, 2010, as well
as U.S. Pat. No. 8,436,185, issued on May 7, 2013 and entitled
Pharmaceutically Acceptable Salts of
2-[4-[3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide, which
claims the benefit of U.S. provisional patent application No.
61/010,333 filed on Jan. 8, 2008, each of which is incorporated
herein by reference.
[0038] The invention also provides pharmaceutical compositions
comprising niraparib and a pharmaceutically acceptable carrier. The
pharmaceutical compositions containing the active ingredient may be
in a form suitable for oral use, for example, as tablets, troches,
lozenges, aqueous or oily suspensions, dispersible powders or
granules, emulsions, hard or soft capsules, or syrups or
elixirs.
[0039] Compositions intended for oral use may be prepared according
to any method. known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving agents in
order to provide pharmaceutically elegant and palatable
preparations. Tablets contain the active ingredient in admixture
with non-toxic pharmaceutically acceptable excipients which are
suitable for the manufacture of tablets. These excipients may be
for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example,
microcrystalline cellulose, sodium croscarmellose, corn starch, or
alginic acid; binding agents, for example starch, gelatin,
polyvinyl-pyrrolidone or acacia, and lubricating agents, for
example, magnesium stearate, stearic acid or talc. The tablets may
be uncoated or they may be coated by known techniques to mask the
unpleasant taste of the drug or delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a water-soluble taste
masking material such as hydroxypropyl-methylcellulose or
hydroxypropylcellulose, or a time delay material such as ethyl
cellulose, cellulose acetate butyrate may be employed.
[0040] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water-soluble carrier such as
polyethyleneglycol or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0041] Aqueous suspensions contain the active material in admixture
with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanal, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose, saccharin or aspartame.
[0042] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as butylated
hydroxyanisol or alpha-tocopherol.
[0043] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.
[0044] The pharmaceutical compositions of the invention may also be
in the form of an oil-in-water emulsion. The oily phase may be a
vegetable oil, for example olive oil or arachisoil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally occurring phosphatides, for
example soy bean lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening, flavoring
agents, preservatives and antioxidants.
[0045] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative,
flavoring and coloring agents and antioxidant. The pharmaceutical
compositions may be in the form of a sterile injectable aqueous
solution. Among the acceptable vehicles and solvents that may be
employed are water, Ringer's solution and isotonic sodium chloride
solution.
[0046] The sterile injectable preparation may also be a sterile
injectable oil-in-water microemulsion where the active ingredient
is dissolved in the oily phase. For example, the active ingredient
may be first dissolved in a mixture of soybean oil and lecithin.
The oil solution then introduced into a water and glycerol mixture
and processed to form a microemulsion.
[0047] The injectable solutions or microemulsions may be introduced
into a patient's blood stream by local bolus injection.
Alternatively, it may be advantageous to administer the solution or
microemulsion in such a way as to maintain a constant circulating
concentration of the instant compound. In order to maintain such a
constant concentration, a continuous intravenous delivery device
may be utilized. An example of such a device is the Deltec
CADD-PLUS.TM. model 5400 intravenous pump.
[0048] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension for
intramuscular and subcutaneous administration. This suspension may
be formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, for example as a
solution in 1,3-butanediol. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose, any bland fixed oil may be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[0049] Niraparib may also be administered in the form of
suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the
rectum to release the drug. Such materials include cocoa butter,
glycerinated gelatin, hydrogenated vegetable oils, mixtures of
polyethylene glycols of various molecular weights and fatty acid
esters of polyethylene glycol.
[0050] For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing the instant compounds are employed.
(For purposes of this application, topical application shall
include mouth washes and gargles.)
[0051] Niraparib can be administered in intranasal form via topical
use of suitable intranasal vehicles and delivery devices, or via
transdermal routes, using those forms of transdermal skin patches
well known to those of ordinary skill in the art. To be
administered in the form of a transdermal delivery system, the
dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen. Niraparib may also be
delivered as a suppository employing bases such as cocoa butter,
glycerinated gelatin, hydrogenated vegetable oils, mixtures of
polyethylene glycols of various molecular weights and fatty acid
esters of polyethylene glycol.
[0052] When niraparib is administered to a subject, the selected
dosage level will depend on a variety of factors including, but not
limited to, the activity of the particular compound, the severity
of the individual's symptoms, the route of administration, the time
of administration, the rate of excretion of the compound, the
duration of the treatment, other drugs, compounds, and/or materials
used in combination, and the age, sex, weight, condition, general
health, and prior medical history of the patient. The amount of
niraparib and route of administration will ultimately be at the
discretion of the physician, although generally the dosage will be
to achieve local concentrations at the site of action which achieve
the desired effect without causing substantial harmful or
deleterious side-effects.
[0053] Administration in vivo can be effected in one dose,
continuously or intermittently (e.g. in divided doses at
appropriate intervals) throughout the course of treatment. Methods
of determining the most effective means and dosage of
administration are well known to those of skill in the art and will
vary with the formulation used for therapy, the purpose of the
therapy, the target cell being treated, and the subject being
treated. Single or multiple administrations can be carried out with
the dose level and pattern being selected by the treating
physician.
[0054] In general, a suitable dose of niraparib is in the range of
about 100 .mu.g to about 250 mg per kilogram body weight of the
subject per day. Where the active compound is a salt, an ester,
prodrug, or the like, the amount administered is calculated on the
basis of the parent compound and so the actual weight to be used is
increased proportionately. A therapeutically effective amount of
niraparib or a pharmaceutical composition thereof for the treatment
of prostate cancer includes a dose range from about 30 mg/day to
about 400 mg/day of niraparib, or any particular amount or range
therein, in particular about 300 mg/day, and once daily oral
administration in three 100 mg oral dosage forms. Optimal dosages
of niraparib to be administered may be readily determined and will
vary with the particular compound used, the mode of administration,
the strength of the preparation and the advancement of the disease,
syndrome, condition or disorder. In addition, factors associated
with the particular subject being treated, including subject
gender, age, weight, diet and time of administration, will result
in the need to adjust the dose to achieve an appropriate
therapeutic level and desired therapeutic effect. The above dosages
are thus exemplary of the average case. There can be, of course,
individual instances wherein higher or lower dosage ranges are
merited, and such are within the scope of this invention.
[0055] Niraparib may be administered in any of the foregoing
compositions and dosage regimens or by means of those compositions
and dosage regimens established in the art whenever use of
niraparib is required for a subject in need thereof.
EXAMPLES
[0056] The following Examples are set forth to aid in the
understanding of the invention, and are not intended and should not
be construed to limit in any way the invention set forth in the
claims which follow thereafter.
Example 1
In Vitro Cytotoxicity of Niraparib in Human Prostate Tumor
Lines
[0057] The cytotoxicity of niraparib was tested in several human
prostate tumor lines in vitro. None of the tumor lines is known to
be BRCA-1 or BRC A-2 deficient.
Methods:
[0058] In vitro cytotoxicity of niraparib was assessed in 5 human
prostate cancer cell lines: C4-2B, LNCaP, LNCaP AR.TB, VCaP, and
22Rv1, C4-2B, LNCaP, LNCaP AR.TB, and 22Rv1 cell lines were grown
in RPMI1640+GlutaMAX.TM.-I medium (Life Technologies #61870-036)
supplemented with 10% heat-inactivated fetal bovine serum (FBS)
(Life Technologies #16140-071) and non-essential amino acids (NEAR)
(Life Technologies #11140-050); and VCaP cells were grown in
DMEM+GlutaMAX.TM.-I medium (Life Technologies ##10569-010) with 10%
FBS and NEAA. VCaP cells were subcultured every 7 days; other lines
were split every 3-4 days.
[0059] Cell growth kinetics of each cell line were determined by
seeding cells at several densities and monitoring growth at
intervals up to 7 days. Growth was determined using the Promega
Cell TiterGlo reagent (#G7571) to measure cellular ATP by means of
a chemiluminescent luciferin-luciferase reaction. Plates were read
on a Perkin-Elmer Envision plate reader, and luminescence values
were plotted in order to identify seeding densities that resulted
in log-phase growth and a cell density within the linear range of
the Cell TiterGlo assay at the desired time point.
[0060] For niraparib cytotoxicity experiments, cells were harvested
by brief trypsinization and each line was seeded to the inner 60
wells of 96-well plates in 100 .mu.L of medium at an appropriate
density for a 7-day treatment. The outer wells of each plate were
filled with Dulbecco's phosphate buffered saline (DPBS; Life
Technologies #14190-144) to reduce evaporation from test wells.
Cells were rested overnight in the plates at 37.degree. C. in a
humidified 5% CO.sub.2 incubator. Treatment was initiated by
addition of 50 .mu.L of 3.times. niraparib (final concentrations
500, 125, 31.3, 7.8, 1.95, 0.49, 0.12, 0.03 .mu.M) in the
appropriate medium to triplicate wells. The final vehicle
concentration was 0.5% DMSO.
[0061] Cells were cultured for 7 days. Relative cell viability
after treatment was determined using Cell TiterGlo reagent, as
above. All luminescent output values were normalized to percent
inhibition based on mean luminescence of the untreated control
wells, and the mean percent inhibition of the vehicle control wells
was subtracted from each treatment value. Percent inhibition was
plotted vs log .mu.M concentration in GraphPad Prism 7.00.
Nonlinear regression and calculation of EC.sub.50 values were
performed using the log(agonist) vs. response--Variable slope (four
parameters) fit.
Results:
[0062] Results of the cytotoxicity assay are shown in FIG. 1 and
Table 1. Growth of each cell line was reduced in a dose-dependent
fashion by increasing concentrations of niraparib. C4-2B cells
appeared to be the most sensitive, with an EC.sub.50 value of
.about.1.2 .mu.M. VCaP cells appeared to be the least sensitive
with an EC.sub.50 value of 4.1 .mu.M.
TABLE-US-00001 TABLE 1 EC.sub.50 values for 7-day niraparib
treatment of human prostate tumor cell lines. Cell Line EC.sub.50,
.mu.M C4-2B 1.222 LNCaP 3.502 LNCaP AR.TB 2.140 VCaP 4.099 22Rv1
3.517
Example 2
Inhibition of PAR Formation by Niraparib
[0063] The ability of niraparib to inhibit the formation of
poly(ADP)ribose (PAR) was tested in two human prostate tumor lines
in vitro. Neither of the tumor lines is known to be BRCA-1 or
BRCA-2 deficient.
Methods:
[0064] PAR inhibition using niraparib was assessed in 2 human
prostate cancer cell lines, C4-2B and VCaP. The C4-2B cell line was
grown in RPMI1640+GlutaMAX.TM.-I medium supplemented with 10% :MS
and NEAA and split every 3-4 days. VCaP cells were grown in
DMEM+GlutaMAX.TM.-I medium with EBS and NEAA and subcultured every
7 days.
[0065] Cells were harvested by brief trypsinization and each line
was seeded into 6-well plates in 1 mL of medium at an appropriate
density. An extra 500 .mu.L of complete medium was added, for a
total volume per well of 1.5 mL. Cells were rested overnight in the
plates at 37.degree. C. in a humidified 5% incubator. The next day,
medium was removed from plates and cells were washed using 1 mL
serum free medium (RPMI or DMFM respectively). Treatment was
initiated by addition of 1 mL of niraparib (final concentrations
100, 10, 1, 0.1, 0.01 and 0 .mu.M in 0.1% DMSO) in the appropriate
medium to triplicate wells. Plates were returned to the incubator
for two hours.
[0066] Following treatment, extracts were prepared using reagents
and procedures provided in the HT PARP in vivo Pharmacodynamic
Assay II (Trevigen #4520-096-K). Medium was removed from each well
and placed into separate labeled microfuge tubes, and the plates
were placed on ice. The tubes were spun at 1500 rpm for 4 minutes
to pellet any cells that detached from the plate during drug
incubation. Lysis buffer was prepared using 24.5 mL of cell lysis
reagent with 250 .mu.L of 100 mM PMSF (in ethanol; Sigma #93482)
and 250 .mu.L 100.times. Protease Inhibitor Cocktail (Thermo
Scientific #78429). Lysis buffer (300 .mu.L) was added to each well
of the plates, on ice. Adherent cells were scraped into lysis
buffer and kept on ice for at least 15 minutes. Supernatant was
removed from the microfuge tubes, and the cell lysates from the
6-well plates were added to each tube from the corresponding tubes.
SDS (20% w/v) was added to bring the final SDS concentration to 1%.
The cell extracts were heated to 95-100.degree. C. for 5 minutes.
After cooling to room temperature, 0.01 volume of 100.times.
magnesium cation and 3 .mu.L DNase were added to each tube. Tubes
were briefly vortexed and returned to a 37.degree. C. incubator for
90 minutes. After the incubation, tubes were centrifuged at 10,000
'g for 10 minutes at room temperature. If a pellet was present, it
was removed using a pipette tip and extracts were transferred to a
96 well dilution plate. Cell extracts were frozen at -80.degree. C.
until used for protein quantitation and the PAR ELISA assay. The
ELISA assay protocol was performed according to the manufacturer's
instructions.
[0067] Protein quantitation was performed using the
detergent-compatible Biorad DC protein assay kit II (#500-0002)
with the Biorad Quick. Start Bovine Serum Albumin Standard Set
(#5000207) according to the manufacturer's 96-well plate protocol.
ELISA lysis buffer was spiked into the standards, and an equal
volume of PBS was added to all sample wells to correct for any
effect of the lysis buffer on protein readings. Samples were
assayed in duplicate. Buffer A' (25 .mu.L) was added to all wells
of the plate, and 200 .mu.L of Buffer B was immediately added to
each well. Plates were incubated for 15 minutes at room temperature
on a shaker. Absorbance was read at 750 nm on a Molecular Devices
M5 plate reader, using the DC Protein Assay protocol in SoftMax Pro
version 6.3 software. Linear regression of the standard curve,
interpolation of sample protein values, and replicate averaging
were performed in the software. Data was exported to Excel, where
any corrections for sample dilution were performed.
[0068] Luminescence values of PAR ELISA standards and samples were
analyzed in GraphPad Prism version 7, where linear regression of
the standard curve and interpolation of sample values were
calculated. Interpolated PAR. values (pg PAR/mL) were corrected for
sample dilution and divided by the corresponding protein
concentration to yield pg PAR/mg of protein. These values were
graphed in GraphPad Prism v7.
Results:
[0069] The results from the PAR assay are shown in FIG. 2. PAR was
reduced in a dose-dependent fashion by increasing concentrations of
niraparib in each cell line.
Example 3
Niraparib Induces .gamma.-H2AX in Human Prostate Tumor Lines In
Vitro
[0070] The ability of niraparib to induce double stranded breaks in
DNA was measured in 3 human prostate cancer cell lines 22RV1, LNCaP
AR.TB, and C4-2B. Double stranded breaks in DNA are followed by
phosphorylation of adjacent histone .gamma.-H2AX, and this
phosphorylation can be measured by antibody staining and flow
cytometry.
Methods:
[0071] 22RV1, LNCaP AR.TB, and C4-2B cell lines were grown as
outlined above. Cell lines were passaged every 3-4 days.
[0072] For each cell line, 2.times.10.sup.5 cells were seeded in
each well of a 12-well plate (Falcon #353043) in a volume of 1 mL
of media. Cells were rested overnight in a 37.degree. C. humidified
5% CO.sub.2 incubator, then 1 mL of media containing 2.times.
concentrated serially diluted niraparib was added to achieve final
concentrations of 200, 100, 50, 25, 12.5, 6.25, 3.13, 1.57, 0.78,
0.39, 0.2, and 0.1 .mu.M in triplicate wells. The final vehicle
concentration was 0.2% DMSO) and triplicate wells of vehicle and
media controls were also obtained for each cell line. Plates were
incubated for another 18 hours.
[0073] Following the 18 hour incubation with drug, each well of
cells was harvested by first transferring the 2 mL of media into a
15 mL conical tube (Corning 4430798). 500 .mu.L of cell
dissociation buffer (Gibco #13151-014) was then added to the well
and allowed to sit for 5 minutes. Using a 1 mL pipette, 1 mL of
media was added to the well, cells were dislodged by pipetting, and
the cell-containing media was transferred to the corresponding 15
mL conical tube. Tubes were centrifuged at 1200 rpm for 5 minutes,
the supernatant was discarded, and the pelleted cells were
resuspended and transferred to a 96-well v-bottom plate (Costar
#3896). Plates were centrifuged at 1800 rpm for 3 minutes,
supernatant discarded, then wells were washed with 200 .mu.L of
DPBS. This process was repeated for a total of 3 washes. Cells were
then stained with 100 .mu.L of DPBS containing a 1:800 dilution of
Invitrogen Live/Dead fixable aqua (Invitrogen #L34957) for 20
minutes at 4.degree. C. Cells were then washed with 150 .mu.L BD
Pharmingen Stain Buffer (stain buffer; BD #554657) and centrifuged
at 1800 rpm for 3 minutes. Cells were washed again 2 times with 200
.mu.L stain buffer and then once with DPBS.
[0074] Cells were fixed with 100 .mu.L-20.degree. C. 70%
ethanol/H.sub.2O and plates were stored at -20.degree. C. for 2
hours. Cells were washed 3 times with stain buffer centrifuging at
2200 rpm for 3 minutes between each wash. Cells were then incubated
with 100 .mu.L of a 1:1 dilution stain buffer and AXELL biotin-free
Fc receptor blocker (Accurate Chemical & Scientific Corp
#N9309) for 20 minutes at 4.degree. C. Cells were washed with 150
.mu.L of stain buffer then centrifuged at 2200 rpm for 3 minutes,
supernatant discarded, then cells were incubated with 50 .mu.L
stain buffer containing 0.2% v/v Triton X-100 (Acros Organics
#21568-2500) for 2 hours at room temperature in the dark along with
1:100 dilutions of .gamma.-H2AX antibody (Biolegend #613408).
[0075] Cells were washed once with 200 .mu.L stain buffer
containing 0.2% v/v Triton X-100, and then washed once with 200
.mu.L stain buffer only. Cells were resuspended in 80 .mu.L of
stain buffer and 50 .mu.L was analyzed on a BD Fortessa flow
cytometer. Data were analyzed using TreeStar FlowJo v9.8.5. Data
was gated on live cells, then following doublet discrimination, the
entire population was assessed for .gamma.-H2AX antibody signal.
Results were graphed In GraphPad Prism v7.
Results:
[0076] Representative histograms for the 22RV1 cell line are shown
in FIG. 3, depicting the effect of different concentrations of
niraparib. Drug-treated samples were compared to vehicle and media
controls and are graphed in FIG. 4. The lowest concentrations where
.gamma.-H2AX signal rises significantly above vehicle control are
indicated in Table 2. The results show that, in each prostate tumor
line, niraparib induces .gamma.-H2AX in a dose-dependent
manner.
TABLE-US-00002 TABLE 2 Minimum concentration of niraparib that
induces significant change in .gamma.-H2AX 1.sup.st Significant
Cell line Concentration (.mu.M) 22RV1 1.57 LnCaP.AR.TB 3.13 C4-2B
1.57
Example 4
[0077] Niraparib Inhibits the Growth of C4-2B Human Prostate Tumors
in Mice
[0078] The activity of niraparib was tested in the pre-established
human prostate subcutaneous C4-2B model in non-obese diabetic (NOD)
severe combined immunodeficient (scid) gamma (NOD.Cg-Prkdc
Il2rg/SzJ) (NSG) mice. This tumor model is not believed to be
BRCA-1 or BRCA-2 deficient.
Methods:
[0079] Vehicle was 0.5% Methyl cellulose (Methocel.TM. F4M)
prepared and kept at 4.degree. C. in the dark. All formulations
were made to be dosed at a volume of 10 ml/kg body weight. NSG male
mice (Jackson Laboratories) were used. Animals were habituated for
one week prior to any experimental procedures being performed. Mice
were group housed (5 per cage) in disposable IVC-cages (Innovive,
San Diego, Calif., USA) under a 12-h light:dark cycle at a
temperature of 19 to 22.degree. C. and 35 to 40% humidity. Mice
were fed an autoclaved high fat (6%) diet laboratory chow and water
ad libitum.
[0080] Mice were injected with LNCaP C4-213-luc tagged cells
(1.times.10.sup.6 tumors cells in a 200 .mu.l volume of
Cultrex.RTM.:RPMI 1640 medium (1:1 ratio) on the right flank. Mice
were randomized per tumor volumes (tumor volume=241.+-.14
mm.sup.3), with 10 mice per treatment group. Mice were dosed daily
by gavage (p.o.) with either vehicle, or vehicle containing
niraparib as indicated below at 10 ml/kg dosing volume. Start of
treatment=Day 1. Mice were treated through study day 24.
[0081] Group 1 0 mg/kg Vehicle (0.5% Methocel F4M) dosed. QD
p.o.
[0082] Group 2 25 mg/kg niraparib in 0.5% Methocel F4M dosed QD
p.o.
[0083] Group 3 50 mg/kg niraparib in 0.5% Methocel F4M dosed. QD
p.o.
[0084] For each individual animal, body weight and tumor volume
[using the formula: Tumor Volume (mm3)=(a.times.b.sup.2/2); where
`a` represents the length, and `b` the width of the tumor as
determined by caliper measurements], were monitored twice weekly
throughout the study. For the pre-established tumors, a time-course
of tumor growth is expressed as mean +standard error of the mean
(SEM).
Results:
[0085] The vehicle treated mice started to reach ethical limits for
tumor volume around study day 22 onwards (see FIG. 5 for individual
tumor volumes). Tumor volume data was presented up to study day 24
(when 9 of 10 vehicle-treated mice remained on study). After 18,
22, and 24 days of treatment, group 3 dosed daily with 50 mg/kg
niraparib p.o. showed significant inhibition/delay in tumor growth,
with tumor growth inhibition (TGI) values of .about.40% on these
days. Significant differences in tumor growth were observed on days
18, 22 and 24 (*p<0.05; **p<0.01; ***p<0.001). Mice dosed
at 25 mg/kg of niraparib did not show significant tumor growth
inhibition, though there was modest TGI of .about.12% on days 22
and 24.
Example 5
[0086] A multicenter, open-label study is carried out to assess the
efficacy and safety of once daily dosing of 300 mg niraparib in
male subjects over the age of 18 years with mCRPC and DNA-repair
anomalies who have had at least one line of taxane-based
chemotherapy and at least one line of antiandrogen therapy (e.g.,
abiraterone acetate, enzalutamide, apalutamide). The study will
enroll approximately 100 subjects. Subjects will be monitored for
safety during the study period, and up to 30 days after the last
dose of study drug. Treatment will continue until disease
progression, unacceptable toxicity, death, or the sponsor
terminates the study.
[0087] The study will consist of 4 phases; a Prescreening Phase for
biomarker evaluation only, a Screening Phase, a Treatment Phase,
and a Follow-up Phase. The efficacy evaluations include the
following: Tumor measurements: chest, abdomen' and pelvis CT or MRI
scans and whole body bone scans (.sup.99mm) serum PSA, survival
status, CTC, and symptomatic skeletal event (SSE).
[0088] Niraparib, 300 mg, will be provided as capsules (3.times.100
mg) for once daily oral administration. The capsules must be
swallowed whole. Subjects should take their dose in the morning
(with or without food). Although not considered study medication,
subjects who have not undergone surgical castration must continue
to receive regularly prescribed GnRHa. All GnRHa therapies should
be recorded in the concomitant medication section of the eCRF.
[0089] A treatment cycle is defined as 28 days. Subjects will begin
taking niraparib on Day 1 of Cycle 1. Sufficient quantities of
niraparib for each treatment cycle will be distributed on the first
day of each cycle. If subjects miss a dose, then that dose should
be replaced if the subject remembers within an approximate 12-hour
window. Otherwise, subjects should take the next dose the following
day, without compensating for the missed dose. Missed doses should
be recorded in the eCRF.
[0090] Prescreening Phase for Biomarker Evaluation
[0091] The Prescreening Phase will evaluate if a potential subject
is biomarker-positive for DNA-repair anomalies. All subjects will
be required to sign a specific ICF for the Prescreening Phase and
provide baseline demographic characteristics and disease-specific
medical history. The Prescreening Phase may occur any time prior to
the Screening Phase.
[0092] The process for determining biomarker-positivity will be
different for subjects who enter the Prescreening Phase before a
blood-based assay is available, compared with those subjects who
enter after a blood-based assay is available. The 2 processes are
described below.
[0093] Process for Determining Biomarker-positivity Before a
Blood-based Assay is Available
[0094] The Subject signs the prescreening ICF. If the subject has
had tumor tissue previously analyzed by the FoundationOne.RTM. gene
panel, then after the subject grants a release, the
FoundationOne.RTM. data can be reviewed to determine eligibility
based on the criteria defined in Table 1 If the subject is
biomarker-positive, they are eligible to enter the Screening Phase.
If the subject has not had tumor tissue previously analyzed by the
FoundationOne.RTM. gene panel, then they must have either archival
or recently collected (recommended) tumor tissue analyzed for
biomarker-positivity by a sponsor-approved test. If the subject is
biomarker-positive, they are eligible to enter the Screening
Phase.
[0095] Blood samples will also be collected from all subjects
during the Prescreening Phase and stored for when a blood-based
assay becomes available. At the time a blood-based assay becomes
available, the stored blood sample will be analyzed for concordance
with the tumor tissue sample results. This analysis may occur at
any time after the blood-based assay becomes available.
[0096] Process for Determining Biomarker-Positivity After a
Blood-Based Assay is Available
[0097] Subject signs the prescreening ICF. Subject has blood
collected and sent for analysis of biomarker-positivity. If the
subject has had tumor tissue previously analyzed by the
FoundationOne.RTM. gene panel, then after the subject grants a
release, the FoundationOne.RTM. data can be reviewed to determine
eligibility based on the criteria defined in Table 1. If the
subject is biomarker-positive, they are eligible to enter the
Screening Phase and do not need to wait for results of the
blood-based analysis. If the FoundationOne.RTM. gene panel is
negative, the subject may still be considered eligible if they are
determined to be biomarker-positive by the blood-based assay. If
the subject has not had tumor tissue previously analyzed by the
FoundationOne.RTM. gene panel and archival tissue is available,
then a request for retrieval and analysis of the archived tumor
tissue is initiated. If the blood-based assay results are
biomarker-positive, then the subject is eligible to enter the
Screening Phase and does not need to wait for results of the
archival tumor tissue-based analysis. The results from the archival
tumor tissue-based analysis, when they are available, may be used
in conjunction with the blood-based results for concordance and
bridging studies.
[0098] At the discretion of the study sponsor, if the blood-based
assay results are negative, then the archival tumor tissue-based
results may be used to determine eligibility.
[0099] If no archival tumor tissue is available, then the subject
must agree to have tumor tissue collected.
[0100] If the blood-based assay results are biomarker-positive,
then the recent tumor tissue must be collected prior to Cycle 1 Day
1 for later use in concordance and bridging studies.
[0101] Analysis of the recently collected tumor tissue may occur
any time during the study and the results may not be required prior
to the subject entering the Screening Phase.
[0102] At the discretion of the study sponsor, if the blood-based
assay results are negative, then the recently collected tumor
tissue may be used to determine eligibility.
[0103] Once subjects are identified as biomarker-positive during
the Prescreening Phase, the Screening Phase should start within 30
days.
[0104] Screening Phase
[0105] All biomarker-positive subjects must sign the main study ICF
prior to the conduct of any study-related procedures in the
Screening Phase. During this phase, eligibility criteria will be
reviewed and a complete clinical evaluation will be performed as
specified in the Time and Events Schedule. Screening procedures
will be performed up to 35 days before Cycle 1 Day 1, unless
otherwise specified, Imaging will be accepted up to 8 weeks prior
to Cycle 1 Day 1. Screening clinical safety laboratory evaluations
can be used for Cycle 1 Day 1 assessments if performed within 14
days of Cycle 1.
[0106] Subjects who do not meet all inclusion criteria, or who meet
an exclusion criterion, may be rescreened once. Rescreening is at
the discretion of the investigator and requires sponsor approval
and agreement. Subjects who are to be rescreened must sign a new
ICF before rescreening. Subjects rescreened within 35 days of
planned enrollment may use the initial screening laboratory
results, computed tomography (CT)/magnetic resonance imaging (MRI)
and bone scans (if still within 8 weeks of Cycle 1 Day 1) to
determine eligibility if not the reason for the rescreening.
[0107] Treatment Phase
[0108] The Treatment Phase will begin at Cycle I Day 1 and will
continue until the study drug is discontinued. The last
measurements taken on Day 1 of Cycle 1 before administration of the
study drug or at screening (whichever value was last) will be
defined as the baseline values. Visits for each cycle will have a
.+-.3-day window, unless otherwise specified. Study visits will be
calculated from the Cycle 1 Day 1 date. Subjects may have imaging
performed within .+-.7 days of visits requiring images. Refer to
the Time and Events Schedule for treatment visits and assessments
during the Treatment Phase.
[0109] For PK and pharmacodynamics sampling days, the subject must
not take the study drug at home on the morning of study visits.
Study drug should be taken at the site. Details of PK and
pharmacodynamics sampling days and times are provided in the Time
and Events Schedule. Additional details regarding PK sampling are
provided in Section Error! Reference source not found. Details of
blood sample handling and storage procedures for PK and
pharmacodynamics are provided in the laboratory manual.
[0110] Clinical evaluations and laboratory studies may be repeated
more frequently, if clinically indicated. Study drug treatment will
continue until disease progression, unacceptable toxicity, death,
or the sponsor terminates the study. Once the subject discontinues
study drug, the subject must complete the End-of-Treatment (EoT)
visit within 30 days after the last dose of study drug, and enter
the Follow-up Phase.
[0111] End-of-Treatment Visit
[0112] An End of Treatment visit must be scheduled within 30 days
after the last dose of study drug or prior to administration of a
new anti-prostate cancer therapy, whichever occurs first. If a
subject is unable to return to the site for the EoT visit, the
subject should be contacted to collect AEs that occurred within 30
days after the last dose of study drug.
[0113] Follow-Up Phase
[0114] Once a subject has completed the Treatment Phase, survival
follow-up and SSEs will be performed every 3 months either via
clinic visits, telephone interview, chart review, or other
convenient methods. Deaths regardless of causality and SAES thought
to be related to study drugs will be collected and reported within
24 hours of discovery or notification of the event. If the
follow-up information is obtained via telephone contact, then
written documentation of the communication must be available for
review in the source documents.
[0115] Biomarker-Positive Sample for DNA-Repair Anomalies
[0116] To evaluate if subjects are biomarker-positive, a
blood-based assay may become available during the study that will
provide a more rapid method than tissue-based analysis for
determining biomarker-positive status, while being more convenient
for the subjects. Prior to the blood-based assay becoming
available, tumor tissue (either archival or recently collected)
will require analysis. To ensure that all subjects, regardless of
when they enter the study, have the same biomarker data available
for analysis (i.e., for concordance and bridging studies), both
tumor tissue and blood samples will be collected from all subjects
who sign the prescreening informed consent form (ICF). The process
for determining biomarker-positivity will be different for subjects
who enter the Prescreening Phase before the blood-based assay is
available, compared with those subjects who enter after the
blood-based assay is available. However, the status of
biomarker-positivity in both tumor tissue and blood will be
assessed for all subjects.
[0117] To be eligible for the study, subjects must be confirmed
biomarker-positive by tumor tissue (either archival or recently
collected), or blood testing when available. The biomarkers of
interest for this study and the biomarker-positivity criteria are
listed in Table 3. Analyses will be performed to define a proxy for
bi-allelic loss (e.g., mutation co-expression frequency with copy
number loss) and these proxies may be used to determine
biomarker-positivity as that information becomes available.
[0118] Circulating Tumor Cells
[0119] Blood samples will be collected in a Cellsave tube at
timepoints specified in the Time and Events Schedule. CTC
enumeration will be evaluated at the central laboratory, to assess
response to study drug.
[0120] Whole Blood for RNA
[0121] Whole blood samples will be collected in a Paxgene tube.
Multiple ribonucleic acid (RNA) transcripts found in prostate
tumors are detectable in the RNA and analysis of these samples will
allow evaluation of potential mechanisms of resistance that may
emerge with niraparib.
[0122] Circulating Tumor DNA
[0123] Plasma samples collected during the course of treatment will
be used to screen for changes in the levels or types of DNA-repair
anomalies observed over time by circulating tumor DNA (ctDNA), and
to monitor for potential markers of resistance to niraparib.
[0124] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *