U.S. patent application number 14/603717 was filed with the patent office on 2015-12-24 for administration of nedd8-activating enzyme inhibitor and hypomethylating agent.
The applicant listed for this patent is MILLENNIUM PHARMACEUTICALS, INC.. Invention is credited to Peter G. Smith.
Application Number | 20150366886 14/603717 |
Document ID | / |
Family ID | 48193039 |
Filed Date | 2015-12-24 |
United States Patent
Application |
20150366886 |
Kind Code |
A1 |
Smith; Peter G. |
December 24, 2015 |
ADMINISTRATION OF NEDD8-ACTIVATING ENZYME INHIBITOR AND
HYPOMETHYLATING AGENT
Abstract
The present disclosure relates to methods for the treatment of
cancer in patients in recognized need of such treatment. The
methods comprise administering to such a patient an NAE inhibitor
or a pharmaceutically acceptable salt thereof, such as
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate (MLN4924) or
{(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]-
amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl)methyl sulfamate
(I-216), and a hypomethylating agent or a pharmaceutically
acceptable salt thereof, such as azacitidine or decitabine. Also
disclosed are medicaments for use in the treatment of cancer.
Inventors: |
Smith; Peter G.; (Arlington,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MILLENNIUM PHARMACEUTICALS, INC. |
Cambridge |
MA |
US |
|
|
Family ID: |
48193039 |
Appl. No.: |
14/603717 |
Filed: |
January 23, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13667641 |
Nov 2, 2012 |
8980850 |
|
|
14603717 |
|
|
|
|
61555049 |
Nov 3, 2011 |
|
|
|
Current U.S.
Class: |
514/43 |
Current CPC
Class: |
A61K 31/706 20130101;
A61P 35/00 20180101; A61K 31/519 20130101; A61K 31/706 20130101;
A61P 43/00 20180101; A61K 31/505 20130101; A61K 31/505 20130101;
A61P 35/02 20180101; A61K 31/519 20130101; A61K 2300/00 20130101;
A61K 45/06 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/706 20060101
A61K031/706; A61K 31/505 20060101 A61K031/505; A61K 31/519 20060101
A61K031/519 |
Claims
1. A method of treating cancer comprising, administering to a
patient in need of such treatment a therapeutically effective total
amount of an NAE inhibitor or a pharmaceutically acceptable salt
thereof, and a hypomethylating agent or a pharmaceutically
acceptable salt thereof.
2. The method of claim 1, wherein the hypomethylating agent is
azacitidine or decitabine, or a pharmaceutically acceptable salt
thereof.
3. The method of claim 2, wherein the hypomethylating agent is
azacitidine or a pharmaceutically acceptable salt thereof.
4. The method of claim 2, wherein the hypomethylating agent is
decitabine or a pharmaceutically acceptable salt thereof.
5. The method of claim 1, wherein the NAE inhibitor is
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or
{(1S,2S,4R)-4-(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]a-
mino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl)methyl sulfamate, or
a pharmaceutically acceptable salt thereof.
6. The method of claim 5, wherein the NAE inhibitor is
((1S,2S,4R)-4-(4-((15)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methy sulfamate or a
pharmaceutically acceptable salt thereof.
7. The method of claim 5, wherein the NAE inhibitor is
{(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]-
amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl)methyl sulfamate, or
a pharmaceutically acceptable salt thereof.
8. The method of claim 6, wherein
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or
pharmaceutically acceptable salt thereof is administered on Days 1,
3, and 5 of a 28-day cycle.
9. The method of claim 8, wherein
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or
pharmaceutically acceptable salt thereof is administered at a dose
of about 20 mg/m.sup.2.
10. The method of claim 8, wherein
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-4H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or
pharmaceutically acceptable salt thereof is administered at a dose
of about 30 mg/m.sup.2.
11. The method of claim 8, wherein
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or
pharmaceutically acceptable salt thereof is administered at a dose
of about 40 mg/m.sup.2.
12. The method of claim 8, wherein
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or
pharmaceutically acceptable salt thereof is administered at a dose
of about 50 mg/m.sup.2.
13. The method of claim 8, wherein
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or
pharmaceutically acceptable salt thereof is administered
intravenously.
14. The method of claim 8, wherein
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or
pharmaceutically acceptable salt thereof is administered
subcutaneously.
15. The method of any one of claim 1, wherein the hypomethylating
agent is azacitidine or a pharmaceutically acceptable salt thereof
and is administered on Days 1, 2, 3, 4, 5, 8 and 9 of a 28-day
cycle.
16. The method of claim 15, wherein the azacitidine or
pharmaceutically acceptable salt thereof is administered at a dose
of about 75 mg/m.sup.2.
17. The method of claim 15, wherein the azacitidine or
pharmaceutically acceptable salt thereof is administered
subcutaneously.
18. The method of claim 15, wherein the azacitidine or
pharmaceutically acceptable salt thereof is administered
intravenously.
19. The method of claim 1, wherein the NAE inhibitor or
pharmaceutically acceptable salt thereof is administered in
combination with the hypomethylating agent or pharmaceutically
acceptable salt thereof in a single dosage form.
20. The method of claim 1, wherein the NAE Inhibitor or
pharmaceutically acceptable salt thereof is administered in
combination with the hypomethylating agent or pharmaceutically
acceptable salt thereof in separate dosage forms.
21. The method of claim 1, wherein the cancer is a hematologic
malignancy.
22. The method of claim 21, wherein the cancer is acute myeloid
leukemia (AML).
23. The method of claim 21, wherein the cancer is myelodysplastic
syndromes (MDS).
24. The method of claim 23, wherein the myelodysplastic syndromes
(MDS) are diagnosed as any of refractory anemia (RA), refractory
anemia with ringed siderblasts (RARS), (refractory anemia with
excess blasts (RAEB), and RAEB in transformation (RAEB-T).
25. The method of claim 24, wherein the diagnosis is predominantly
one type of myelodysplastic syndromes.
26. The method of claim 24, wherein the diagnosis is more than one
type of myelodysplastic syndromes.
27. The method of claim 21, wherein the cancer is diagnosed as any
of chronic myelogenous leukemia (CML), acute lymphoblastic leukemia
(ALL), chronic lymphocytic leukemia (CLL), Hodgkin's disease (HD),
non-Hodgkin's lymphoma (NHL), T-cell lymphoma, multiple myeloma
(MM), Waldenstrom's macroglobulinemia, myelodysplastic syndromes
(MDS), and myeloproliferative syndromes.
28. The method of claim 27, wherein the diagnosis is predominantly
one type of cancer.
29. The method of claim 27, wherein the diagnosis is more than one
type of cancer.
30. A kit for treating cancer in a subject in recognized need
thereof comprising: at least one medicament comprising at least one
dose of an NAE Inhibitor or a pharmaceutically acceptable salt
thereof, and at least one medicament comprising at least one dose
of a hypomethylating agent or a pharmaceutically acceptable salt
thereof; said kit for treating cancer further comprising dosing
instructions for administering the medicaments for treatment of the
subject in recognized need thereof.
Description
[0001] This application claims benefit of priority from U.S.
Provisional Patent Application No. 61/555,049 filed on Nov. 3,
2011.
[0002] Inhibition of NEDD8-activating enzyme (NAE) has been shown
to induce cancer cell death and inhibit the growth of tumors in
xenograft models. See, e.g., T. A. Soucy et al., Nature, 2009, 458,
732-737; T. A. Soucy et al., Clin. Cancer Res., 2009, 15 (12),
3912-3916; and J. E. Brownell et al., Mol. Cell., 2010, 37 (1),
102-111. Reports of Phase I clinical studies of an NAE inhibitor
include R. T. Swords et al., Blood, 2010, 115, 3796-3800; J. S.
Kauh et al., J. Clin. Oncol., 2011, 29, abstract 3013; and S.
Bhatia et al., J. Clin. Oncol., 2011, 29, abstract 8529. Inhibitors
of NAE are described in U.S. patent application Ser. No. 11/346,469
(Publ. No. 2006/0189636, U.S. Pat. No. 7,951,810), Ser. No.
11/700,614 (Publ. No. 2007/0191293) and Ser. No. 11/890,338 (Publ.
No. 2008/0051404, U.S. Pat. No. 8,008,307), each of the
aforementioned publications is hereby incorporated by reference
herein in its entirety. If there is any discrepancy between any of
these documents and the present specification, the present
specification controls.
[0003] Hypomethylatlng agents have been approved by the US Food and
Drug Administration in the treatment of cancer. For example,
VIDAZA.RTM. (azacitidine for injection) is indicated for treatment
of patients with the following French-American-British (FAB)
myelodysplastic syndromes subtypes: refractory anemia (RA) or
refractory anemia with ringed sideroblasts (if accompanied by
neutropenia or thrombocytopenia or requiring transfusions),
refractory anemia with excess blasts (RAEB), refractory anemia with
excess blasts in transformation (RAEB-T), and chronic
myelomonocytic leukemia (CMMoL). DACOGEN.RTM. (decitabine for
injection) is indicated for treatment of patients with
myelodysplastic syndromes (MDS) including previously treated and
untreated, de novo and secondary MDS of all French-American-British
subtypes (refractory anemia, refractory anemia with ringed
sideroblasts, refractory anemia with excess blasts, refractory
anemia with excess blasts in transformation, and chronic
myelomonocytic leukemia) and intermediate-1, Intermediate-2, and
high-risk International Prognostic Scoring System groups.
[0004] The highest possible dose (MTD: maximum tolerated dose) is
typically sought for agents for the treatment of cancer because the
benefit of the treatment is believed to increase with dose. See,
e.g., Y. Lin and W. J. Shih, Biostatistics, 2001, 2 (2), 203-215. A
synergistic combination of agents--that is, a combination of agents
that is more effective than is expected from the effectiveness of
its constituents, without also compounding the treatment side
effects--can provide an opportunity to deliver even greater
efficacy at the MTD. Accordingly, it can be desirable to discover
synergistic combinations of anti-cancer agents in order to treat
cancer patients most effectively, without overloading the patient
with side effects.
[0005] It has now been discovered that the administration of an NAE
inhibitor or a pharmaceutically acceptable salt thereof and a
hypomethylating agent or a pharmaceutically acceptable salt thereof
provides a synergistic effect. Both in vitro and in vivo
synergistic effects were found. In vitro synergy was measured using
The Combination Index (M. C. Berenbaum, J. Theor. Biol., 1985, 114,
413-431), as discussed in further detail below. In vivo synergy was
measured according to a synergy survival method or a synergy tumor
growth method, as discussed in further detail below.
[0006] At least one aspect of the present disclosure relates to
methods of treating cancer comprising administering to a patient in
need of such treatment, a therapeutically effective total amount of
an NAE inhibitor or a pharmaceutically acceptable salt thereof and
a hypomethylating agent or a pharmaceutically acceptable salt
thereof to a subject in need of such treatment.
[0007] At least one aspect of the present disclosure is also
directed towards the use of an NAE inhibitor or a pharmaceutically
acceptable salt thereof with a hypomethylating agent or a
pharmaceutically acceptable salt thereof for treating cancer in a
patient in need of such treatment.
[0008] At least one aspect of the present disclosure relates to a
kit comprising at least one medicament for use in treating cancer
in a subject in recognized need thereof. For example, the kit may
comprise at least one medicament comprising at least one dose of an
NAE inhibitor or a pharmaceutically acceptable salt thereof, and
instructions for administering the at least one medicament with a
hypomethylating agent or a pharmaceutically acceptable salt
thereof, or the kit may comprise at least one medicament comprising
at least one dose of a hypomethylating agent or a pharmaceutically
acceptable salt thereof, and instructions for administering the
medicament with an NAE inhibitor or a pharmaceutically acceptable
salt thereof. In various embodiments, the kit can comprise at least
one medicament comprising at least one dose of an NAE inhibitor or
a pharmaceutically acceptable salt thereof and at least one
medicament comprising at least one dose of a hypomethylating agent
or a pharmaceutically acceptable salt thereof, and instructions for
administering the medicaments. Furthermore, for example, the kit
can comprise anti-cancer actives consisting of at least one
medicament comprising at least one dose of an NAE inhibitor or a
pharmaceutically acceptable salt thereof, and at least one
medicament comprising at least one dose of a hypomethylatlng agent
or a pharmaceutically acceptable salt thereof; said kit for
treating cancer further comprising dosing instructions for
administering the medicaments for treatment of the subject in
recognized need thereof.
[0009] At least one aspect of the present disclosure relates to at
least one medicament for use in treating cancer in a subject in
need of such treatment. For example, the at least one medicament
may comprise an NAE inhibitor or a pharmaceutically acceptable salt
thereof, or a hypomethylating agent or a pharmaceutically
acceptable salt thereof, or a combination thereof.
[0010] At least one aspect of the present disclosure relates to the
use of an NAE Inhibitor or a pharmaceutically acceptable salt
thereof in the manufacture of at least one medicament for treating
cancer, wherein the NAE inhibitor or a pharmaceutically acceptable
salt thereof is administered with a hypomethylating agent or a
pharmaceutically acceptable salt thereof to a patient in need of
such treatment.
[0011] At least one aspect of the present disclosure relates to the
use of a hypomethylating agent or a pharmaceutically acceptable
salt thereof in the manufacture of at least one medicament for
treating cancer, wherein the a hypomethylating agent or a
pharmaceutically acceptable salt thereof is administered with an
NAE inhibitor or a pharmaceutically acceptable salt thereof to a
patient in need of such treatment.
BRIEF DESCRIPTION OF THE FIGURES
[0012] FIG. 1 shows the Combination index values for NAE inhibitors
MLN4924 and I-216, each separately in combination with azacitidine
or decitabine in HL60, OCIM2, NB4 and THP-1 cell lines.
[0013] FIG. 2 shows a plot of tumor volume as a function of time in
an HL-60 subcutaneous xenograft model following subcutaneous
treatment with: the vehicle alone, MLN4924 as a single agent,
azacitidine ("Aza") as a single agent, and co-administration (s.c.)
of MLN4924 and azacitidine, on Days 1, 4, 8, 11, 15 and 18 at the
indicated doses.
[0014] FIG. 3 shows a plot of tumor volume as a function of time in
a THP-1 subcutaneous xenograft model following subcutaneous
treatment with: the vehicle alone, MLN4924 as a single agent,
azacitidine ("Aza") as a single agent, and co-administration (s.c.)
of MLN4924 and azacitidine, on Days 1, 4, 8, 11, 15 and 18 at the
Indicated doses.
[0015] FIG. 4 shows a plot of tumor volume as a function of time in
a OCI-M2 subcutaneous xenograft model following subcutaneous
treatment with: the vehicle alone, MLN4924 as a single agent,
azacitidine ("Aza") as a single agent, and co-administration (s.c.)
of MLN4924 and azacitidine, on Days 1, 4, 8, 11, 15 and 18 at the
indicated doses.
[0016] FIG. 5 shows a plot of percentage survival as a function of
time in an HL60 disseminated model following subcutaneous treatment
with: the vehicle alone, MLN4924 as a single agent, azacitidine
("AzaC") as a single agent, and co-administration (s.c.) of MLN4924
and azacitidine on Days 22, 25, 29, 32, 36, 39 at the indicated
doses.
[0017] The following definitions and abbreviations may be used
herein: [0018] ALP alkaline phosphatase [0019] ALT alanine
aminotransferase [0020] AML acute myelogenous leukemia [0021] ANC
absolute neutrophil count [0022] AST aspartate aminotransferase
[0023] AUC area under the plasma concentration versus time curve
[0024] BSA body surface area [0025] CR complete response [0026] CRM
continual reassessment method [0027] CYP cytochrome P450 [0028]
DLBCL diffuse large B-cell lymphoma [0029] DLT dose-limiting
toxicity [0030] LFT liver function tests [0031] LVEF left
ventricular ejection fraction [0032] MDS myelodysplastic syndromes
[0033] MM multiple myeloma [0034] MTD maximum tolerated dose [0035]
NAE Nedd8-activating enzyme [0036] NEDD8 neural precursor cell
expressed, developmentally down-regulated 8 [0037] PASP pulmonary
artery systolic pressure [0038] PR partial response [0039] QD once
daily [0040] SCLC small cell lung cancer
[0041] As used herein, "dose-limiting toxicity" (DLT) is defined as
a negative event considered by the administering physician to be
related to therapy with MLN4924 such that the administering
physician believes the doses should be limited in quantity or
altogether stopped. Examples of such events include: [0042] Grade 4
neutropenia (ANC <500 cells/mm.sup.3) lasting more than 7
consecutive days [0043] Grade 3 neutropenia with fever and/or
infection, where fever is defined as an oral temperature
.gtoreq.38.5.degree. C. [0044] Grade 4 thrombocytopenia (platelets
<25,000/mm.sup.3 but >10,000/mm.sup.3) lasting more than 7
consecutive days [0045] Grade 3 thrombocytopenia with bleeding
[0046] A platelet count <10,000/mm.sup.3 at any time [0047]
Grade 3 or greater nausea and/or emesis despite the use of optimal
anti-emetic prophylaxis (wherein "optimal anti-emetic prophylaxis"
is defined as an anti-emetic regimen that employs a 5-HT.sub.3
antagonist given in standard doses and according to standard
schedules). Dexamethasone should not be used because of its
CYP3A-inducing effects. [0048] Grade 3 or greater diarrhea that
occurs despite maximal supportive therapy [0049] An absolute
reduction in LVEF of .ltoreq.10% to a value <50% (e.g., LVEF=45%
in a patient with LVEF=55% at baseline) [0050] A decrease in LVEF
to <40% [0051] An increase in PASP to >50 mm Hg or 3.times.
baseline [0052] Any other Grade 3 or greater nonhematologic
toxicity with the following exceptions: [0053] Grade 3
arthralgia/myalgia [0054] Brief (<1 week) Grade 3 fatigue [0055]
Grade 3 fever that occurs in the absence of Grade 3 or worse
neutropenia or documented infection following daily administration
of MLN4924 [0056] Treatment delay of more than 1 week because of a
lack of adequate recovery of MLN4924-related hematological or
nonhematologic toxicities [0057] MLN4924-related toxicity that
requires that any doses of MLN4924 are missed during a cycle or
discontinuation of therapy with MLN4924
[0058] As used herein, "clinically effective amount" and
"therapeutically effective" means an amount of a therapeutic
substance that is sufficient upon appropriate administration over
an appropriate period of time to a patient (a) to cause a
detectable decrease in the severity of the disorder or disease
state being treated; (b) to ameliorate or alleviate the patient's
symptoms of the disease or disorder; or (c) to slow or prevent
advancement of, or otherwise stabilize or prolong stabilization of,
the disorder or disease state being treated (for instance, to
prevent additional tumor growth or inhibit the cell growth of a
cancer).
[0059] When more than one therapeutic substance is being
administered, the "clinically effective total amount" or
"therapeutically effective total amount" means that the sum of the
individual amounts of each therapeutic substance meets the
definition of "clinically effective amount" even if the individual
amounts of any number of the individual therapeutic substances
would not. For example, if 10 mg of A were not a clinically
effective amount, and 20 mg of B were not a clinically effective
amount, but the administration of 10 mg A+20 mg B resulted in at
least one of the results enumerated for the definition of
"clinically effective amount," then the sum of 10 mg A+20 mg B
would be considered a "clinically effective total amount."
[0060] In any form or composition, the administered dose(s) or the
clinically effective (total) amount can be expressed as amount(s)
of therapeutic substance(s) per patient BSA, e.g., as mg/me.
[0061] As used herein, "patient" means a human being diagnosed
with, exhibiting symptoms of or otherwise believed to be afflicted
with a disease, disorder or condition and thus in recognized need
of the treatment described herein.
[0062] As used herein, the illustrative terms "include," "such as,"
"for example" and the like (and variations thereof, e.g.,
"includes" and "including," "examples"), unless otherwise
specified, are intended to be non-limiting. That is, unless
explicitly stated otherwise, such terms are intended to imply "but
not limited to," e.g., "including" means including but not limited
to.
[0063] As used herein, "body surface area" (BSA) is calculated
using a standard nomogram, e.g.,
BSA ( m 2 ) = Ht ( cm ) .times. Wt ( kg ) 3600 or BSA = Ht ( cm )
.times. Wt ( kg ) 3600 ##EQU00001##
Therapeutic Substances--NAE inhibitors.
[0064] The compound
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]--
pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate:
##STR00001##
also known as MLN4924, has been reported to be an inhibitor of
NEDD8-activating enzyme (NAE). See, e.g., T. A. Soucy et al.,
Nature, 2009, 458, 732-737; T. A. Soucy et al., Clin. Cancer Res.,
2009, 15 (12), 3912-3916; and J. E. Brownell et al., Mol. Cell.,
2010, 37 (1), 102-111. As discussed above, MLN4924,
pharmaceutically acceptable salts thereof, pharmaceutical
compositions of MLN4924 or a pharmaceutically acceptable salt
thereof, processes for synthesis, and polymorphic forms thereof
have been described previously. See, e.g., U.S. patent application
Ser. No. 11/700,614 (Publ. No. 2007/0191293), Ser. No. 12/221,399
(Publ. No. 2009/0036678) and Ser. No. 12/779,331 (Publ. No.
2011/0021544). MLN4924 Drug Substance ("MLN4924-DS") is the
hydrochloride salt of MLN4924, i.e.,
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate
hydrochloride.
[0065] The compound
{(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]-
amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl
sulfamate:
##STR00002##
also known as 1-216, has also been reported to be an inhibitor of
NAE. See U.S. patent application Ser. No. 13/592,389, filed Aug.
23, 2012, claiming priority to U.S. Provisional Patent Appl. No.
61/526,830, filed Aug. 24, 2011, which are hereby incorporated by
reference herein in their entirety. If there is any discrepancy
between these documents and the present specification, the present
specification controls.
Therapeutic Substances--Hypomethylating Agents.
[0066] Azacitidine is
4-amino-1-.beta.-D-ribofuranosyl-s-triazin-2(1H)-one (IUPAC name:
4-amino-1-.beta.-D-ribofuranosyl-1,3,5-triazin-2(1H)-one):
##STR00003##
As discussed above, VIDAZA.RTM. (azacitidine for injection, Celgene
Corporation (Summit, N.J.); VIDAZA.RTM. is a registered trademark
of Celgene Corporation) is indicated and approved by the US FDA for
treatment of patients with the following French-American-British
(FAB) myelodysplastic syndromes subtypes: refractory anemia (RA) or
refractory anemia with ringed sideroblasts (if accompanied by
neutropenia or thrombocytopenia or requiring transfusions),
refractory anemia with excess blasts (RAEB), refractory anemia with
excess blasts in transformation (RAEB-T), and chronic
myelomonocytic leukemia (CMMoL). Full prescribing Information for
VIDAZA.RTM. is available in the commercial package insert.
[0067] Decitabine is
4-amino-1-(2-deoxy-.beta.-D-erythropentofuranosyl)-1,3,5-triazin-2(1H)-on-
e:
##STR00004##
[0068] DACOGEN.RTM. (decitabine for injection, Elsai, Inc.,
Woodcliff Lake, N.J.; DACOGEN.RTM. is a registered trademark of
SuperGen, Inc., Dublin, Calif.) is indicated and approved by the US
FDA for treatment of patients with myelodysplastic syndromes (MDS)
including previously treated and untreated, de novo and secondary
MDS of all French-American-British subtypes (refractory anemia,
refractory anemia with ringed sideroblasts, refractory anemia with
excess blasts, refractory anemia with excess blasts in
transformation, and chronic myelomonocytic leukemia) and
intermediate-1, intermediate-2, and high-risk international
Prognostic Scoring System groups. Full prescribing information for
DACOGEN.RTM. is available in the commercial package insert.
Compound Administration
[0069] It has now been discovered that the administration of an NAE
inhibitor or a pharmaceutically acceptable salt thereof and a
hypomethylating agent or a pharmaceutically acceptable salt thereof
can provide a synergistic effect.
[0070] The NAE inhibitor or a pharmaceutically acceptable salt
thereof (NAEI) can be administered in combination with the
hypomethylating agent or a pharmaceutically acceptable salt thereof
(HMA) in a single dosage form or as a separate dosage form. When
administered as a separate dosage form, the hypomethylating agent
or a pharmaceutically acceptable salt thereof can be administered
prior to, at the same time as, or following administration of the
NAE inhibitor or a pharmaceutically acceptable salt thereof. As
used herein, the administration in "combination" of NAEI and HMA
refers not only to simultaneous or sequential administration of the
two agents, but also to the administration of both compounds during
a single treatment cycle, as understood by one skilled in the
art.
[0071] In some embodiments, the present disclosure relates to
treating cancer in a patient by administering to the patient an NAE
inhibitor or a pharmaceutically acceptable salt thereof (NAEI) and
a hypomethylating agent or a pharmaceutically acceptable salt
thereof (HMA) according to a 28-day cycle as follows: administer
NAEI on Days 1, 4, 8 and 11; and administer HMA on Days 1, 2, 3, 4,
5, 8 and 9. Optionally, the first cycle is 35 days with
administration of NAEI on Days 1, 4, 11 and 15 and administration
of HMA on Days 8, 9, 10, 11, 12, 15 and 16, with subsequent cycles
of 28 days as described in the preceding sentence.
[0072] In some embodiments, the present disclosure-relates to
treating cancer in a patient by administering to the patient an NAE
inhibitor or a pharmaceutically acceptable salt thereof (NAEI) and
a hypomethylating agent or a pharmaceutically acceptable salt
thereof (HMA) according to a 28-day cycle as follows: administer
NAEI on Days 1, 3, and 5; and administer HMA on Days 1, 2, 3, 4, 5,
8 and 9. Optionally, the first cycle is 35 days with administration
of NAEI on Days 1, 3, and 5 and administration of HMA on Days 8, 9,
10, 11, 12, 15 and 16, with subsequent cycles of 28 days as
described in the preceding sentence.
[0073] In various embodiments, the NAEI may be
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]p-
yrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate ("MLN4924") or
((1S,2S,4R)-4-[(6-{(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]a-
mino}pyrimidin-4-yl)oxy)-2-hydroxycyclopentyl)methyl sulfamate
("I-216"). In at least one embodiment, the NAEI is MLN4924. In at
least one embodiment, the NAEI is 1-216.
[0074] In various embodiments, the HMA may be azacitidine or
decitabine. In at least one embodiment, the HMA is azacitidine. In
at least one embodiment, the HMA is decitabine.
[0075] In various embodiments, MLN4924 is administered in
combination with azacitidine. In various embodiments, MLN4924 is
administered in combination with decitabine. In various
embodiments, I-216 is administered in combination with azacitidine.
In various embodiments, I-216 is administered in combination with
decitabine.
[0076] In various embodiments, the NAEI Is administered at a dose
of about 20 mg/m.sup.2, 30 mg/m.sup.2, 40 mg/m.sup.2, 45
mg/m.sup.2, 50 mg/m.sup.2, 60 mg/m.sup.2 or 75 mg/m.sup.2. In
various embodiments, the HMA is administered at a dose of about 75
mg/m.sup.2.
[0077] In various embodiments, the NAEI is administered
intravenously. In various embodiments, the NAEI is administered
orally. In various embodiments, the NAEI Is administered
subcutaneously. In various embodiments, the HMA is administered
intravenously or subcutaneously.
[0078] In some embodiments, the present disclosure relates to
treating cancer in a patient by administering to the patient an
NAEI and a hypomethylating agent HMA according to a 28-day cycle as
follows: administer the NAEI on Days 1, 4, 8 and 11; and administer
HMA on Days 1, 2, 3, 4, 5, 8 and 9; wherein the NAEI is MLN4924 and
HMA is azacitidine; wherein MLN4924 is administered intravenously
at a dose of about 20 mg/m.sup.2, 30 mg/m, 40 mg/m.sup.2, 45
mg/m.sup.2, 60 mg/m.sup.2 or 75 mg/m.sup.2; wherein azacitidine is
administered at a dose of about 75 mg/m.sup.2; and wherein the
cancer is a hematologic malignancy. In various embodiments, the
hematologic malignancy is acute myeloid leukemia (AML) or
myelodysplastic syndromes (MDS). In various embodiments, the
hematologic malignancy is AML. In various embodiments, the
hematologic malignancy is MDS.
[0079] In some embodiments, the present disclosure relates to
treating cancer in a patient by administering to the patient an
NAEI and a hypomethylating agent HMA according to a 28-day cycle as
follows: administer the NAEI on Days 1, 3, and 5; and administer
HMA on Days 1, 2, 3, 4, 5, 8 and 9; wherein the NAEI is MLN4924 and
HMA is azacitidine; wherein MLN4924 is administered intravenously
at a dose of about 20 mg/m.sup.2, 30 mg/m.sup.2, 40 mg/m.sup.2, 45
mg/m.sup.2, 50 mg/m.sup.2, 60 mg/ma or 75 mg/m.sup.2; wherein
azacitidine is administered at a dose of about 75 mg/m.sup.2; and
wherein the cancer is a hematologic malignancy. In various
embodiments, the hematologic malignancy is acute myelold leukemia
(AML) or myelodysplastic syndromes (MDS). In various embodiments,
the hematologic malignancy is AML. In various embodiments, the
hematologic malignancy is MDS.
Therapeutic Substance; Pharmaceutical Compositions.
[0080] The therapeutic substance can be a pharmaceutically
acceptable salt. In some embodiments, such salts are derived from
inorganic or organic acids or bases. For reviews of suitable salts,
see, e.g., Berge et al., J. Pharm. Sci., 1977, 66, 1-19 and
Remington: The Science and Practice of Pharmacy, 20th Ed., A.
Gennaro (ed.), Lippincott Williams & Wilkins (2000).
[0081] Examples of suitable acid addition salts include acetate,
adipate, alginate, aspartate, benzoate, benzene sulfonate,
bisulfate, butyrate, citrate, camphorate, camphor sulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate,
pivalate, propionate, succinate, tartrate, thiocyanate, tosylate
and undecanoate.
[0082] Examples of suitable base addition salts include ammonium
salts; alkali metal salts, such as sodium and potassium salts;
alkaline earth metal salts, such as calcium and magnesium salts;
salts with organic bases, such as dicyclohexylamine salts,
N-methyl-D-glucamine; and salts with amino acids such as arginine,
lysine, and the like.
[0083] For example, Berge lists the following FDA-approved
commercially marketed salts: anions acetate, besylate
(benzenesulfonate), benzoate, bicarbonate, bitartrate, bromide,
calcium edetate (ethylenediaminetetraacetate), camsylate
(camphorsulfonate), carbonate, chloride, citrate, dihydrochloride,
edetate (ethylenediaminetetraacetate), edisylate
(1,2-ethanedisulfonate), estolate (lauryl sulfate), esylate
(ethanesulfonate), fumarate, gluceptate (glucoheptonate),
gluconate, glutamate, glycollylarsanilate
(glycollamidophenylarsonate), hexylresorcinate, hydrabamine
(N,N'-di(dehydro-abietyl)ethylenediamine), hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isethionate
(2-hydroxyethanesulfonate), lactate, lactobionate, malate, maleate,
mandelate, mesylate (methanesulfonate), methylbromide,
methylnitrate, methylsulfate, mucate, napsylate
(2-naphthalenesulfonate), nitrate, pamoate (embonate),
pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,
stearate, subacetate, succinate, sulfate, tannate, tartrate,
teoclate (8-chlorotheophyllinate) and triethlodide; organic cations
benzathine (N,N'-dibenzylethylenediamine), chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine; and metallic cations aluminum, calcium, lithium,
magnesium, potassium, sodium and zinc.
[0084] Berge additionally lists the following non-FDA-approved
commercially marketed (outside the United States) salts: anions
adipate, alginate, aminosalicylate, anhydromethylenecitrate,
arecoline, aspartate, bisulfate, butylbromide, camphorate,
digluconate, dihydrobromide, disuccinate, glycerophosphate,
hemisulfate, hydrofluoride, hydrolodide, methylenebls(salicylate),
napadisylate (1,5-naphthalenedisulfonate), oxalate, pectinate,
persulfate, phenylethylbarbiturate, picrate, propionate,
thiocyanate, tosylate and undecanoate; organic cations benethamine
(N-benzylphenethylamine), clemizole
(1-p-chlorobenzyl-2-pyrrolildine-1'-ylmethylbenzimidazole),
diethylamine, piperazine and tromethamine
(tris(hydroxymethyl)aminomethane); and metallic cations barium and
bismuth.
[0085] As used herein, "pharmaceutically acceptable carrier" refers
to a material that is compatible with a recipient subject (a
mammal, for Instance a human) and is suitable for delivering an
active agent to the target site without terminating the activity of
the agent. The toxicity or adverse effects, if any, associated with
the carrier are, for example, commensurate with a reasonable
risk/benefit ratio for the intended use of the active agent.
[0086] The pharmaceutical compositions for use in the methods of
the present disclosure can be manufactured by methods such as
conventional granulating, mixing, dissolving, encapsulating,
lyophilizing, or emulsifying processes, among others. Compositions
can be produced in various forms, including granules, precipitates,
or particulates, powders, including freeze dried, rotary dried or
spray dried powders, amorphous powders, tablets, capsules, syrup,
suppositories, injections, emulsions, elixirs, suspensions or
solutions. Formulations can contain stabilizers, pH modifiers,
surfactants, solubilizing agents, bioavailability modifiers and
combinations of these.
[0087] Pharmaceutically acceptable carriers that can be used in
these compositions include ion exchangers, alumina, aluminum
stearate, lecithin, serum proteins, such as human serum albumin,
buffer substances such as phosphates or carbonates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
[0088] These pharmaceutical compositions are formulated for
pharmaceutical administration to a mammal, such as a human being.
Such compositions can be administered orally, parenterally, by
inhalation spray, topically, rectally, nasally, buccally,
vaginally, or via an implanted reservoir. The term "parenteral" as
used herein includes subcutaneous, intravenous, intraperitoneal,
intramuscular, intra-articular, intra-synovial, Intrasternal,
intrathecal, intrahepatic, intralesional and intracranial injection
or infusion techniques. In some embodiments, the compositions are
administered orally, intravenously, or subcutaneously. In some
embodiments, the compositions are administered orally. In some
embodiments, the compositions are administered intravenously. These
formulations can be designed to be short-acting, fast-releasing, or
long-acting. Furthermore, the compositions can be administered in a
local rather than systemic means, such as administration (e.g., by
injection) at a tumor site.
[0089] Pharmaceutical formulations can be prepared as liquid
suspensions or solutions using a liquid, such as an oil, water, an
alcohol, and combinations of these. Solubilizing agents such as
cyclodextrins can be included. Pharmaceutically suitable
surfactants, suspending agents, or emulsifying agents, can be added
for oral or parenteral administration. Suspensions can include
oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and
olive oil. Suspension preparations can also contain esters of fatty
acids such as ethyl oleate, Isopropyl myristate, fatty acid
glycerides and acetylated fatty acid glycerides. Suspension
formulations can include alcohols, such as ethanol, isopropyl
alcohol, hexadecyl alcohol, glycerol and propylene glycol; ethers,
such as poly(ethyleneglycol); petroleum hydrocarbons such as
mineral oil and petrolatum; and water.
[0090] Sterile injectable forms of these pharmaceutical
compositions can be aqueous or oleaginous suspensions. These
suspensions can be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation can 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. Among the Illustrative vehicles and solvents that
can be employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose, any bland fixed oil can be employed including synthetic
mono- or di-glycerides. Fatty acids, such as oleic add and its
glyceride derivatives are useful in the preparation of injectables,
as are natural pharmaceutically-acceptable oils, such as olive oil
or castor oil, for instance in their polyoxyethylated versions.
These oil solutions or suspensions can also contain a long-chain
alcohol diluent or dispersant, such as carboxymethyl cellulose or
similar dispersing agents which are commonly used in the
formulation of pharmaceutically acceptable dosage forms Including
emulsions and suspensions. Other commonly used surfactants, such as
Tweens, Spans and other emulsifying agents or bioavailability
enhancers which are commonly used in the manufacture of
pharmaceutically acceptable solid, liquid, or other dosage forms
can also be used for the purposes of formulation. Compounds can be
formulated for parenteral administration by Injection such as by
bolus injection or continuous infusion. A unit dosage form for
injection can be in ampoules or in multi-dose containers.
[0091] For example, in various embodiments of the present
disclosure, the NAEI is MLN4924 Injection Drug Product
("MLN4924-IDP"). MLN4929-IDP is formulated with the following
excipients: citric acid; sodium hydroxide; Cyclodextrin
Sulfobutylethers, Sodium Salts (Captisol.RTM.); and water for
injection. In at least one embodiment, MLN4929-IDP consists of 10
mg/mL MLN4924 (as free base) In a solution containing 50 mM citrate
buffer and 100 mg/mL sulfobutylether .beta.-cyclodextrin, pH
3.3.
[0092] MLN4924-IDP has experienced stability problems when diluted
in saline. MLN4924-IDP can be used for the duration of the retest
period indicated on the Certificate of Analysis. In practice,
MLN4924-IDP has been stored refrigerated at 5.degree.
C..+-.3.degree. C. Each Type I glass vial nominally contains 5 mL
of compounded sterile solution, sealed with a Teflon.RTM.-coated
butyl rubber stopper and oversealed with an aluminum seal with a
plastic Flip-Off.RTM. cap.
[0093] In various embodiments of the present disclosure, the HMA is
azacitidine. Azacitidine is commercially available VIDAZA.RTM.
(azacitidine for injection), which is supplied as lyophilized
powder in 100-mg single-use vials. Refer to the VIDAZA.RTM. package
Insert for additional information.
[0094] These pharmaceutical compositions can be orally administered
in any orally acceptable dosage form including capsules, tablets,
aqueous suspensions or solutions. When aqueous suspensions are
required for oral use, the active ingredient can be combined with
emulsifying and suspending agents. If desired, certain sweetening,
flavoring or coloring agents can also be added. For oral
administration in a capsule form, useful diluents include lactose
and dried cornstarch. In the case of tablets for oral use, carriers
that are commonly used include lactose and corn starch. Lubricating
agents, such as magnesium stearate, are also typically added.
Coatings may be used for a variety of purposes, e.g., to mask
taste, to affect the site of dissolution or absorption, or to
prolong drug action. Coatings can be applied to a tablet or to
granulated particles for use in a capsule.
[0095] Alternatively, these pharmaceutical compositions can be
administered in the form of suppositories for rectal
administration. These can be prepared by mixing the agent with a
suitable non-irritating excipient which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0096] These pharmaceutical compositions can also be administered
topically, for Instance when the target of treatment includes areas
or organs readily accessible by topical application, including
diseases of the eye, the skin, or the lower intestinal tract.
Suitable topical formulations are readily prepared for each of
these areas or organs.
[0097] Topical application for the lower intestinal tract may be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches can also
be used. For topical applications, the pharmaceutical compositions
can be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of the present
disclosure include mineral oil, liquid petrolatum, white
petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene
compound, emulsifying wax and water. Alternatively, the
pharmaceutical compositions can be formulated in a suitable lotion
or cream containing the active component(s) suspended or dissolved
in at least one pharmaceutically acceptable carrier. Suitable
carriers include mineral oil, sorbitan monostearate, polysorbate
60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl
alcohol and water.
[0098] For ophthalmic use, the pharmaceutical compositions can be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, for instance, as solutions in Isotonic, pH
adjusted sterile saline, either with our without a preservative
such as benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions can be formulated in an
ointment such as petrolatum.
[0099] The pharmaceutical compositions can also be administered by
nasal aerosol or Inhalation. Such compositions can be prepared
according to techniques known in the art of pharmaceutical
formulation and can be prepared as solutions in saline, employing
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, fluorocarbons, and/or other
conventional solubilizing or dispersing agents.
[0100] The methods disclosed herein can be used to treat diseases,
disorders, and conditions in which Inhibition of NAE enzyme
activity is detrimental to survival and/or expansion of diseased
cells or tissue (e.g., cells are sensitive to NAE inhibition;
inhibition of NAE activity disrupts disease mechanisms; reduction
of NAE activity stabilizes protein which are Inhibitors of disease
mechanisms; reduction of NAE activity results in inhibition of
proteins which are activators of disease mechanisms). The diseases,
disorders and conditions can also include those which require
effective cullin and/or ubiquitination activity, which activity can
be regulated by diminishing NAE enzyme activity.
[0101] For example, the methods disclosed herein can be useful in
treatment of disorders involving cellular proliferation, including
disorders which require an effective cullin-dependent
ubiquitination and proteolysis pathway (e.g., the ubiquitin
proteasome pathway) for maintenance and/or progression of the
disease state. The methods of the present disclosure can be useful
in treatment of disorders mediated via proteins (e.g., NF.kappa.B
activation, p27.sup.Kip activation, p21.sup.wAF/CP1 activation, p53
activation) which are regulated by NAE activity. Representative
disorders include proliferative disorders, most notably cancers and
inflammatory disorders (e.g., rheumatoid arthritis, inflammatory
bowel disease, asthma, chronic obstructive pulmonary disease
(COPD), osteoarthritis, dermatosis (e.g., atopic dermatitis,
psoriasis), vascular proliferative disorders (e.g.,
atherosclerosis, restenosis) autoimmune diseases (e.g., multiple
sclerosis, tissue and organ rejection)); as well as inflammation
associated with infection (e.g., immune responses),
neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's
disease, motor neuron disease, neuropathic pain, triplet repeat
disorders, astrocytoma, and neurodegeneration as result of
alcoholic liver disease), ischemic injury (e.g., stroke), and
cachexia (e.g., accelerated muscle protein breakdown that
accompanies various physiological and pathological states, (e.g.,
nerve injury, fasting, fever, acidosis, HIV infection, cancer
affliction, and certain endocrinopathies)).
[0102] The methods disclosed herein can be useful, for Instance,
for the treatment of cancer. As used herein, the term "cancer"
refers to a cellular disorder characterized by uncontrolled or
disregulated cell proliferation, decreased cellular
differentiation, inappropriate ability to invade surrounding
tissue, and/or ability to establish new growth at ectopic sites.
The term "cancer" includes solid tumors and bloodborne tumors. The
term "cancer" encompasses diseases of skin, tissues, organs, bone,
cartilage, blood, and vessels. The term "cancer" further
encompasses primary and metastatic cancers.
[0103] In some embodiments, the cancer is a solid tumor. Examples
of solid tumors that can be treated by the methods of the present
disclosure include pancreatic cancer; bladder cancer; colorectal
cancer; breast cancer, Including metastatic breast cancer; prostate
cancer, including androgen-dependent and androgen-independent
prostate cancer; renal cancer, including, e.g., metastatic renal
cell carcinoma; hepatocellular cancer; lung cancer, including,
e.g., small cell lung cancer (SCLC), non-small cell lung cancer
(NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of
the lung; ovarian cancer, including, e.g., progressive epithelial
or primary peritoneal cancer; cervical cancer; gastric cancer;
esophageal cancer; head and neck cancer, including, e.g., squamous
cell carcinoma of the head and neck; melanoma; neuroendocrine
cancer, including metastatic neuroendocrine tumors; brain tumors,
including, e.g., glioma, anaplastic oligodendroglioma, adult
glioblastoma multiforme, and adult anaplastic astrocytoma; bone
cancer; and soft tissue sarcoma.
[0104] In some embodiments, the cancer is a hematologic malignancy.
Examples of hematologic malignancy include acute myelold leukemia
(AML); chronic myelogenous leukemia (CML), including accelerated
CML and CML blast phase (CML-BP); acute lymphoblastic leukemia
(ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD);
non-Hodgkin's lymphoma (NHL), including follicular lymphoma and
mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple
myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastlc
syndromes (MDS), including refractory anemia (RA), refractory
anemia with ringed siderblasts (RARS), (refractory anemia with
excess blasts (RAEB), and RAEB in transformation (RAEB-T); and
myeloproliferative syndromes.
[0105] In some embodiments, a physician may diagnose a patient with
a cancer as predominantly one type. In some embodiments, a
physician may diagnose a patient as having more than one type of
cancer. In some embodiments, the diagnosis is predominantly one
type of myelodysplastic syndromes. In some embodiments, the
diagnosis is more than one type of myelodysplastic syndromes.
[0106] In some embodiments, methods of the present disclosure are
used to treat a patient having, or at risk of developing or
experiencing, a recurrence in a tumor cancer, such as colorectal
cancer, ovarian cancer, lung cancer, breast cancer, gastric cancer,
prostate cancer and pancreatic cancer. In some embodiments, methods
of the present disclosure are used to treat a patient having, or at
risk of developing or experiencing, a recurrence in a hematologic
cancer, such as AML, CML, CML-BP, ALL, or CLL.
[0107] In order that this disclosure be more fully understood, the
following examples are set forth. These examples are illustrative
only and are not intended to limit the scope of the present
disclosure in any way.
EXAMPLES
1. In Vitro Cell Viability Assays
[0108] The experimental protocol used Poly-D-lysine BloCoat.TM.
Black/Clear 384 plates (Becton Dickinson, Franklin Lakes, N.J.).
The appropriate NAE inhibitor was dissolved in DMSO and delivered
Into the wells using an Echo (Labcyte, Sunnyvale, Calif.) liquid
handling system. HL60 and THP-1 lines were obtained from ATCC
(American Type Culture Collection, Manassas, Va.), while NB4 and
OCI-M2 lines were obtained from DSMZ (Deutsche Sammlung von
Mikroorganismen und Zellkulturen GmbH, Brunswick, Germany). Each
plate had a cell suspension from one of the lines added to the
wells. A portion of the wells were used as positive controls (no
compound was added), while another portion of the wells were used
as negative controls (no cells were added). The plates were
incubated for 72 hours, and then the cell viabilities were measured
using an ATPlite (PerkinElmer, Waltham, Mass.) assay.
Statistical Analyses.
[0109] Normalization. The viability data was normalized separately
for each plate by scaling the data so that the median of the
negative controls was 0 and the median of the positive controls was
100. More formally,
V i = 100 U i - median ( U - ) median ( U + ) - median ( U - )
##EQU00002##
where V.sub.i is the normalized viability of the i.sup.th well,
U.sub.i is the raw viability measurement, median (U.sub.-) is the
median of the negative controls, and median(U.sub.+) is the median
of the positive controls. After normalization, the controls were
discarded.
[0110] Response surface model and fitting. A response surface model
was used to describe the relationship between the normalized
viability and the drug concentrations. For a given plate, let
C=(C.sub.A/I.sub.1)+(C.sub.B/I.sub.2)
x=(C.sub.A/I.sub.1)/C
E.sub.max=E.sub.1+E.sub.2x+E.sub.3x.sup.2+E.sub.4x.sup.3
I=1+I.sub.3x(1-x)
S=S.sub.1+S.sub.2x+S.sub.3x.sup.2+S.sub.4x.sup.3
V=100-E.sub.max(1+(I/C).sup.S).sup.-1+error
where E.sub.1, E.sub.2, E.sub.3, E.sub.4, I.sub.1, I.sub.2,
I.sub.3, S.sub.1, S.sub.2, S.sub.3, and S.sub.4 are parameters,
C.sub.A and C.sub.B are the respective concentrations of drugs A
and B, and V is the normalized viability measurement. It was
assumed that the error values were independent and identically
distributed normal random variables. This model is an extension of
the Hill equation (A. V. Hill, J. Physiol., 1910, 40, iv-vii),
which is commonly used to model the effect of a single drug. The
data were fitted to this model using the maximum likelihood method
with the statistical software program R R Development Core Team
(2008) (R: A language and environment for statistical computing. R
Foundation for Statistical Computing, Vienna, Austria. ISBN
3-900051-07-0, URL http://www.R-project.org).
[0111] Quality checks. Three types of quality checks were applied
to the plates. First, it was checked that the variation of the
positive controls and the mean of the negative controls were small.
Next, it was checked that the new data agreed with data from
previous single drug experiments. Finally, the residuals from the
response surface fit were analyzed to ensure that the residual sum
of squares was sufficiently small. All of these quality checks were
based on numerical thresholds to make pass/fail decisions, and the
same thresholds were used for all of the plates in the experiment.
If a plate failed any one of the quality checks, It was removed
from the analysis.
[0112] Measuring in vitro synergy. The Combination index (M. C.
Berenbaum, J. Theor. Biol., 1985, 114, 413-431) was used as a
measure of drug synergy. The Combination Index is computed based on
an isobologram, which is a slice of the dose response surface with
constant viability. For the present analysis, the 50% isobologram,
which is the dose contour that has 50% viability, was used. The
EC50.sub.A and EC50.sub.B are defined be the respective doses of
drugs A and B alone that have a viability of 50%. For a point
(D.sub.A, D.sub.B) along the 50% Isobologram, the Combination Index
is defined as (D.sub.A/EC50.sub.A)+(D.sub.B/EC50.sub.B). Since the
choice of (D.sub.A, D.sub.B) can be arbitrary, the constraint
D.sub.A/D.sub.B=EC50.sub.A/EC50.sub.B was used. If the Combination
Index is less than 1, it Indicates that the isobologram curves
inward, and that the drug combination is synergistic. Conversely,
if the Combination Index Is greater than 1, the 50% isobologram
curves outward, indicating antagonism. In the more stringent
analysis method applied according to the present disclosure,
Combination Index values within the range 0.8-1.2 are considered
additive. This rule prevents small deviations from additivity from
being classified as synergistic.
[0113] A two sided t-test for each condition was performed to
determine if the mean Combination index differed from 1. The
Benjaminl-Hochberg method (Y. Benjamini and Y. Hochberg, J. R.
Stat. Soc., Series B (Stat. Methodol.), 1995, 57 (1), 289-300) was
used to adjust the resulting p-values for multiple hypothesis
testing. An adjusted p-value below 0.05 was considered to
statically significant. In order for a combination to be classified
as synergistic, we required that three criteria be met: the mean
Combination Index for the condition had to be less than 1, the
difference had to be statistically significant, and Combination
Index had to be outside the range (0.8, 1.2). This third criterion
prevented small deviations from additivity from being classified as
synergistic. Combinations for which the p-value was above 0.05 or
the Combination Index was within the range (0.8, 1.2) were
classified as additive.
[0114] Cell viability assays were used to assess the combination
effect in vitro of each of two NAE inhibitors, MLN4924 and I-216,
with each of two hypomethylating agents, azacitidine and
decitabine, in four cell lines, HL60, OCIM2, NB4, and THP-1. FIG. 1
shows the Combination Index for all of the experiments that passed
the quality checks among each tested combination. The results are
arranged by the condition. Table 1, below, lists the mean
Combination Index, the adjusted p-value, and the conclusion for
each determined combination. As Table 1 shows, all eight
combinations of NAE Inhibitor and hypomethylating agent
demonstrated a synergistic effect in both the OCIM2 and NB4 cell
lines. In the HL60 line, both NAE inhibitors demonstrated synergy
with decitabine and showed an additive effect with azacitidine. In
the THP-1 line, both NAE inhibitors demonstrated an additive effect
with azacitidine. Due to the lack of single agent activity of
decitabine in THP-1, a Combination Index cannot be calculated for
the in vitro experiments with NAE inhibitors and decitabine in
THP-1.
TABLE-US-00001 TABLE 1 Summary of the Combination Index values.
Number of Mean NAE Hypomethylating passing Combination Adjusted
inhibitor agent Cell line plates Index P-value Conclusion MLN4924
Decitabine HL60 6 0.45 6.2 .times. 10.sup.-4 Synergy I-216
Decitabine HL60 4 0.46 5.8 .times. 10.sup.-3 Synergy MLN4924
Azacitidine HL60 5 1.03 1.1 .times. 10.sup.-1 Additivity I-216
Azacitidine HL60 3 0.97 4.9 .times. 10.sup.-1 Additivity MLN4924
Decitabine OCIM2 7 0.52 1.4 .times. 10.sup.-4 Synergy I-216
Decitabine OCIM2 5 0.45 4.0 .times. 10.sup.-5 Synergy MLN4924
Azacitidine OCIM2 5 0.44 4.8 .times. 10.sup.-6 Synergy I-216
Azacitidine OCIM2 3 0.41 2.7 .times. 10.sup.-3 Synergy MLN4924
Decitabine NB4 5 0.61 1.4 .times. 10.sup.-4 Synergy I-216
Decitabine NB4 4 0.61 2.7 .times. 10.sup.-3 Synergy MLN4924
Azacitidine NB4 4 0.52 5.8 .times. 10.sup.-3 Synergy I-216
Azacitidine NB4 4 0.56 5.3 .times. 10.sup.-3 Synergy MLN4924
Decitabine THP-1 4 NA NA NA I-216 Decitabine THP-1 4 NA NA NA
MLN4924 Azacitidine THP-1 4 1.10 2.4 .times. 10.sup.-2 Additivity
I-216 Azacitidine THP-1 4 1.11 2.7 .times. 10.sup.-2 Additivity
[0115] FIG. 1 shows the Combination Index values for each plate,
arranged by the condition (i.e., a given drug combination applied
to a given cell line). These results were summarized by computing
the mean Combination Index for each condition, as shown in Table
1.
2. In Vivo Tumor Efficacy Models
Subcutaneous Xenograft Models
[0116] Test subjects. HL-60 (2.times.10.sup.6) tumor cells in 100
.mu.L phosphate buffered saline with Matrigel.TM. (BD Biosciences,
Bedford, Mass.) were aseptically injected into the subcutaneous
space in the right dorsal flank of female Ncr nude mice (age 5-8
weeks, Charles River Laboratories, Wilmington, Mass.) using a
26-gauge needle. THP-1 (2.5.times.10.sup.6) or OCI-M2
(5.times.10.sup.6) tumor cells in 100 .mu.L phosphate buffered
saline with Matrigel.TM. were aseptically injected into the
subcutaneous space in the right dorsal flank of female CB.17 SCID
mice (age 5-8 weeks, Charles River Laboratories) using a 26-gauge
needle.
[0117] Beginning on day seven (7) after Inoculation, tumors were
measured twice weekly using a vernier caliper. Tumor volumes were
calculated using standard procedures
(0.5.times.(length.times.width.sup.2)). When the tumors reached a
volume of approximately 200 mm.sup.3, mice were randomized into
groups of 10 and injected subcutaneously with compound inhibitor
(200 .mu.L) at various doses and schedules, with the first dosing
day defined as Day 1. All control groups received vehicle alone.
Tumor size and body weight were measured approximately twice a week
for the duration of the study. Mice were euthanized when their
tumor volume reached 10% of their body weight, or when the average
tumor volume of a treatment or control group reached approximately
2000 mm.sup.3. The dosing schedule for each study was as follows:
MLN4924 and azacitidine were dosed separately or co-dosed by
subcutaneous injection on Days 1, 4, 8, 11, 15 and 18 at the
indicated doses. Tumor growth continued to be monitored after the
dosing period. Average tumor volume reported as a function of time
is shown in FIGS. 2-4.
[0118] Statistical Analyses of Synergy for Tumor Growth in
Subcutaneous Xenograft Models.
[0119] For the THP-1 and OCI-M2 models, measurements from day 0 to
21 were analyzed. For the HL60 model, measurements from day 0 to 14
were used, since several of the mice had tumors exceeding the
allowed volume after day 14. All tumor volumes had a value of 1
added to them before log.sub.20 transformation. These values were
compared across treatment groups to assess whether the differences
in the trends over time were statistically significant. To compare
pairs of treatment groups, the following mixed-effects linear
regression model was fit to the data using the maximum likelihood
method:
Y.sub.ijk-Y.sub.i0k=Y.sub.i0k+treat.sub.i+day.sub.j+day.sub.j.sup.2+(tre-
at*day).sub.ij+(treat*day.sup.2).sub.ij+e.sub.ijk
where Y.sub.ijk is the log.sub.10 tumor value at the j.sup.th time
point of the k.sup.th animal in the i.sup.th treatment, Y.sub.i0k
is the day 0 log.sub.10 tumor value in the k.sup.th animal in the
i.sup.th treatment, day.sub.j was the median-centered time point
and was treated as a continuous variable, and e.sub.ijk is the
residual error. A spatial power law covariance matrix was used to
account for the repeated measurements on the same animal over time.
Interaction terms as well as day.sub.j.sup.2 terms were removed if
they were not statistically significant.
[0120] A likelihood ratio test was used to assess whether a given
pair of treatment groups exhibited differences which were
statistically significant. The -2 log likelihood of the full model
was compared to one without any treatment terms (reduced model) and
the difference in the values was tested using a Chi-squared test.
The degrees of freedom of the test were calculated as the
difference between the degrees of freedom of the full model and
that of the reduced model.
[0121] In addition to the statistical significance, a measure of
the magnitude of the effect for each treatment was found. The
predicted differences in the log tumor values (Y.sub.ijk-Y.sub.i0k)
vs. time were taken from the above model to calculate mean area
under the curve (AUC) values for each treatment group. A dAUC value
was then calculated as:
dAUC = 100 mean ( AUC control ) - mean ( AUC treatment ) mean ( AUC
control ) ##EQU00003##
[0122] For synergy analyses, the observed differences in the log
tumor values were used to calculate AUC values for each animal. In
instances when an animal in a treatment group was removed from the
study, the last observed tumor value was carried forward through
all subsequent time points. To Improve the robustness of the
synergy analysis, the following procedure was applied to the AUC
values from each treatment group. Let x be the set of AUC values
for a given treatment group. A range of interest was defined:
(median(x)-5*MAD(x), median(x)+5*MAD(x)).
Here, MAD is the median absolute deviation of x. If any value in x
fell outside this range, that value was replaced by the value at
the closest boundary. The procedure was non-iterative, so the range
was computed only once for each treatment group.
[0123] The synergy score for the combination of treatments A and B
was defined as
100*(mean(AUC.sub.AB)-mean(AUC.sub.A)-mean(AUC.sub.B)+mean(AUC.sub.ctl))-
/mean(AUC.sub.ctl)
where AUC.sub.AB, AUC.sub.A, AUC.sub.B, and AUC.sub.ctl are the AUC
values for animals in the combination group, the A group, the B
group, and the control group, respectively. The standard error of
the synergy score was computed based on the variation in the AUC
values among the animals. A two sided t-test was used to determine
if the synergy score was significantly different from zero. If the
P-value was below 0.05, and the synergy score was less than zero,
then the combination was considered to be synergistic. If the
P-value was above 0.05, then the combination was considered to be
additive.
[0124] Mouse xenograft models were used to assess the combination
effect in vivo of NAE inhibitor MLN4924 and hypomethylating agent
azacitidine. FIGS. 2-4 show tumor volume as a function of time in
three subcutaneous xenograft models following treatment with the
vehicle as a single agent, MLN4924 as a single agent, azacitidine
("Aza") as a single agent, and co-administration (s.c.) of MLN4924
and azacitidine on Days 1, 4, 8, 11, 11, 15 and 18 at the Indicated
doses.
[0125] In the HL-60 subcutaneous xenograft model (FIG. 2), MLN4924
and azacitidine as single agents had a marginal effect on tumor
growth. In contrast, co-dosing MLN4924 and azacitidine led to tumor
regressions, with a statistical assessment of synergy.
[0126] In the THP-1 xenograft model (FIG. 3), azacitidine as single
agent had a marginal effect on tumor growth whereas MLN4924 as a
single agent inhibited tumor growth. In contrast, co-dosing MLN4924
and azacitidine led to tumor regressions. Despite the statistical
assessment of additivity in this model, rather than synergy, the
figure clearly shows a combination benefit: tumor growth inhibition
(single agent) versus tumor regression with the combination.
[0127] An additional demonstration of improved activity in THP-1 is
the delay in tumor regrowth with the combination compared to each
single agent. The additional benefit provided by the combination
over the single agent treatments was statistically significant, as
shown in Table 3b (P-value <0.05).
[0128] In the OCI-M2 subcutaneous xenograft model (FIG. 4), MLN4924
and azacitidine as single agents inhibited tumor growth. In
contrast, co-dosing MLN4924 and azacitidine led to tumor
regressions with a statistical assessment of synergy.
Disseminated Xenograft Model
[0129] Test subjects. HL-60 (1.times.10.sup.7) tumor cells in 100
.mu.L IMDM media were inoculated in the lateral vein of female mice
CB-17 SCID (age 8-10 weeks, Charles River Laboratories, Wilmington,
Mass.) using a 27-gauge needle. On day 20 post-inoculation, mice
were randomized into groups of 10. Starting on day 22, mice were
dosed subcutaneously with vehicle, 180 mg/kg MLN4924, 10 mg/kg
azacitidine, or the combination of 180 mg/kg MLN4924 and 10 mg/kg
azacitidine, using the same twice-weekly schedule as described in
the subcutaneous xenograft experiments (dosing on days 22, 25, 29,
32, 36, 39). The mice were monitored at least twice weekly for body
weight loss and signs of disease, including paresis or paralysis of
hind limbs and emergence of palpable and internal solid tumors. The
day on which an animal died or was sacrificed due to disease burden
was recorded. Survival time is shown in FIG. 5.
Statistical Analysis of Synergy for Survival in Disseminated
Xenograft Model.
[0130] To determine synergy in the survival times, the mean
survival times and corresponding standard errors were computed for
each treatment group. The survival synergy was defined as
mean(survival.sub.AB)-mean(survival.sub.A)-mean(survival.sub.B)+mean(sur-
vival.sub.ctl)
where survival.sub.AB, survival.sub.A, survival.sub.B, and
survival.sub.ctl are the survival times for animals in the
combination group, the A group, the B group, and the control group,
respectively. The standard error for the survival synergy was found
by adding the standard error of each of the four terms in
quadrature. A two sided Z-test was used to determine if the
survival synergy was significantly different from zero. If the
P-value was below 0.05, and the survival synergy was greater than
zero, then the combination was considered to be synergistic, if the
P-value was above 0.05, then the combination was considered to be
additive.
[0131] FIG. 5 shows survival as a function of time in a
disseminated xenograft model in which HL-60 cells were inoculated
by intravenous injection, and mice were treated with vehicle, with
MLN4924 as a single agent, azacitidine as a single agent, and
co-administration of s.c. MLN4924 and azacitidine beginning on Day
22 post-inoculation at the indicated doses, using the same
twice-weekly schedule as in the experiments in FIGS. 2-4. In the
HL-60 disseminated model (FIG. 5), MLN4924 and azacitidine as
single agents both extended mean survival time compared to the
control group (8.4 day extension for MLN4924 and 21.1 day extension
for azacitidine). The combination of MLN4924 and azacitidine
extended mean survival time by 36.7 days, which is 7.2 days longer
than would be expected from an additive combination (FIG. 5). The
survival synergy was statistically significant.
TABLE-US-00002 TABLE 2A Synergy assessment for HL60 subcutaneous
xenograft tumors. Synergy Sunergy score Treatment score standard
error P-Value Assessment MLN4924 180 mg/kg + azacitidine 15 mg/kg
-54.8 17.6 0.005 Synergy
TABLE-US-00003 TABLE 2B Pairwise comparison of treatment groups for
HL60 subcutaneous xenograft tumors. P-Value for the Reference
Treated dAUC difference in effects MLN4924 180 mg/kg MLN4924 180
mg/kg + azacitidine 15 mg/kg 118.3 <0.001 azacitidine 15 mg/kg
MLN4924 180 mg/kg + azacitidine 15 mg/kg 112.9 <0.001
TABLE-US-00004 TABLE 3A Synergy assessment for THP-1 subcutaneous
xenograft tumors. Synergy Synergy score Treatment score standard
error P-Value Assess MLN4924 180 mg/kg + azacitidine 10 mg/kg -40.5
21.4 0.078 Additive
TABLE-US-00005 TABLE 3B Pairwise comparison of treatment groups for
THP-1 subcutaneous xenograft tumors. P-Value for the Reference
Treated dAUC difference in effects MLN4924 180 mg/kg MLN4924 180
mg/kg + azacitidine 10 mg/kg 882.2 <0.001 azacitidine 10 mg/kg
MLN4924 180 mg/kg + azacitidine 10 mg/kg 221.1 <0.001
TABLE-US-00006 TABLE 4A Synergy assessment for THP-1 subcutaneous
xenograft tumors. Synergy score Treatment Synergy score standard
error P-Value Assessment MLN4924 180 mg/kg + azacitidine 5 mg/kg
-52.1 15.1 0.002 Synergy
TABLE-US-00007 TABLE 4B Pairwise comparison of treatment groups for
OCI-M2 subcutaneous xenograft tumors. P-Value for the Reference
Treated dAUC difference in effects MLN4924 180 mg/kg MLN4924 180
mg/kg + azacitidine 5 mg/kg 545.5 <0.001 azacitidine 5 mg/kg
MLN4924 180 mg/kg + azacitidine 5 mg/kg 767.6 <0.001
TABLE-US-00008 TABLE 5A Mean survival times for mice with HL-60
disseminated xenograft model Mean Standard error survival of mean
survival Treatment time (days) time (days) Vehicle 48.1 1.0 MLN4924
180 mg/kg 56.5 0.7 azacitidine 10 mg/kg 69.2 2.1 MLN4924 180 mg/kg
+ 84.8 2.4 azacitidine 10 mg/kg
TABLE-US-00009 TABLE 5B Survival time synergy assessment for HL-60
disseminated xenograft model. Survival Survival synergy Treatment
synergy (days) standard error (days) P-Value Assess MLN4924 180
mg/kg + azacitidine 10 mg/kg 7.2 3.4 0.036 Synergy
Prophetic Drug Administration Example.
[0132] Prior to use, MLN4924-IDP vials are warmed to ambient
conditions (15.degree. C. to 30.degree. C.) by placing them at room
temperature. Accelerated warming methods, such as a water bath, was
not, and must not be, used. MLN4924-IDP is stable at room
temperature for 8 hours prior to dilution.
[0133] Each MLN4924-IDP vial contains nominally 5 mt (50 mg MLN4924
as free base). Using sterile technique, the appropriate volume of
drug Is withdrawn from vial(s) and injected into a 250 mL IV bag
containing a 5% dextrose solution, which is then gently inverted
repeatedly to mix. The prepared MLN4924-IDP IV bag must be used
within 6 hours if stored at room temperature. Alternatively, the
prepared IV bag is chemically stable and can be stored for up to 24
hours at 5.degree. C..+-.3.degree. C. After 24 hours of storage at
5.degree. C..+-.3.degree. C., the prepared IV bag must be used
within 6 hours upon coming to room temperature. The vial must not
be shaken at any time during dose preparation.
[0134] Instructions for the preparation, reconstitution, and
dispensation of azacitidine are provided in the azacitidine
(VIDAZA.RTM.) package Insert
[0135] The amount of MLN4924 and azacitidine administered is based
on body surface area (BSA). BSA is calculated using a standard
nomogram on Cycle 1, Day 1, and at subsequent visits if the patient
experiences a >5% change in body weight from the weight used for
the most recent BSA calculation.
[0136] Patients receive MLN4924 diluted with 5% dextrose in a
250-mL IV bag via a 60-minute infusion. MLN4924 should be
administered through central or peripheral venous access. The
infusion can be slowed or stopped and restarted for any associated
infusion reactions. The total infusion time must not exceed six
hours from the time of reconstitution.
[0137] The entire content of the MLN4924 IV bag will be infused at
a constant rate over 1 hour. To ensure that all the MLN4924 enters
the body, the infusion line will be flushed with 5% dextrose
immediately after administration.
[0138] Instructions for the administration of azacitidine are
provided in the azacitidine (VIDAZA.RTM.) package Insert.
[0139] Although DLTs can occur at any point during treatment, only
DLTs occurring during Cycle 1 of treatment will necessarily
influence decisions regarding dose escalation, expansion of a dose
level, or evaluation of Intermediate dose levels. Patients are
monitored through all cycles of therapy for treatment-related
toxicities.
[0140] The duration of cycles will be 28 days. Azacitidine will be
administered in a 5-on/2-off/2-on schedule, i.e., on Days 1, 2, 3,
4, 5, 8, and 9. MLN4924 will be administered on Days 1, 3, and 5.
Patients will receive both agents on Days 1, 3 and 5. MLN4924 can
be administered at a dose of 20 mg/m.sup.2, 30 mg/m.sup.2, 40
mg/m.sup.2, 45 mg/m.sup.2, 50 mg/m.sup.2, 60 mg/m.sup.2, or 75
mg/m.sup.2. Azacitidine will be administered either IV or SC at a
dose of 75 mg/m.sup.2.
[0141] In an optional embodiment, MLN4924 will be administered on
Days 1, 8, and 15.
[0142] Optionally, the duration of cycles will be 28 days, with the
exception of Cycle 1, where a 7-day lead-in will be incorporated
where no azacitidine will be administered, such that Cycle 1 will
last a total of 35 days. According to this schedule, azacitidine
will be administered in a 5-on/2-off/2-on schedule; on Days 8 to 12
and Days 15 and 16 In Cycle 1, and on Days 1, 2, 3, 4,5, 8, and 9
for all subsequent cycles. According to this schedule, MLN4924 will
be administered on Days 1, 3, and 5.
[0143] In an another optional embodiment, MLN4924 will be
administered on Days 1, 4, 11 and 15 for Cycle 1 only, giving one
35 day cycle; in all subsequent cycles, MLN4924 will be
administered on Days 1, 3, and 5, each cycle lasting 28 days.
According to this optional schedule, patients will receive both
agents on Days 11 and 15 of Cycle 1 and on Days 1, 3, and 5 of
subsequent cycles. MLN4924 will be administered at a dose of 20
mg/m.sup.2, 30 mg/m.sup.2, 40 mg/m.sup.2, 45 mg/m.sup.2, 50
mg/m.sup.2, 60 mg/m.sup.2, or 75 mg/m.sup.2. Azacitidine will be
administered either IV or SC (physician's choice) at a dose of 75
mg/m.sup.2.
[0144] Patients will receive azacitidine as either an IV or SC
injection (see azacitidine [VIDAZA.RTM.]package insert for details
on administration). On days where both MLN4924 and azacitidine are
to be administered, infusion of MLN4924 will commence at a time
ranging from 15 to 60 minutes after completion of administration of
azacitidine. An assessment of vital signs will be made pre
azacitidine dose, pre MLN4924 dose, and post MLN4924 dose on these
days.
* * * * *
References