U.S. patent application number 17/279765 was filed with the patent office on 2022-02-03 for methods of treating myeloproliferative disorders.
The applicant listed for this patent is Impact Biomedicines, Inc.. Invention is credited to Tymara Berry, John Hood, Catriona Jamieson, Curtis L. Scribner.
Application Number | 20220031699 17/279765 |
Document ID | / |
Family ID | |
Filed Date | 2022-02-03 |
United States Patent
Application |
20220031699 |
Kind Code |
A1 |
Berry; Tymara ; et
al. |
February 3, 2022 |
METHODS OF TREATING MYELOPROLIFERATIVE DISORDERS
Abstract
The present disclosure provides methods of mitigating thiamine
deficiency.
Inventors: |
Berry; Tymara; (Morristown,
NJ) ; Hood; John; (Del Mar, CA) ; Jamieson;
Catriona; (La Jolla, CA) ; Scribner; Curtis L.;
(Oakland, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Impact Biomedicines, Inc. |
Summit |
NJ |
US |
|
|
Appl. No.: |
17/279765 |
Filed: |
September 24, 2019 |
PCT Filed: |
September 24, 2019 |
PCT NO: |
PCT/US2019/052608 |
371 Date: |
March 25, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62783076 |
Dec 20, 2018 |
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62736369 |
Sep 25, 2018 |
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International
Class: |
A61K 31/51 20060101
A61K031/51; A61P 35/02 20060101 A61P035/02; A61K 31/675 20060101
A61K031/675 |
Claims
1. A method of treating a myeloproliferative disorder, comprising
(i) administering to a patient in need thereof Compound I, or a
pharmaceutically acceptable salt or hydrate thereof; and (ii)
monitoring the patient's thiamine levels; wherein the patient's
thiamine levels are adjusted if the level of thiamine is below a
reference standard.
2. The method of claim 1, wherein the patient's thiamine levels are
assessed by analyzing one or more biomarkers for thiamine
deficiency.
3. The method of claim 2, wherein the biomarker for thiamine
deficiency is a serum thiamine level.
4. The method of claim 2 or claim 3, wherein the level of the
biomarker following administration of Compound I is lower than the
reference standard
5. The method of any of claims 1-4, wherein the patient's thiamine
levels are adjusted by administering to the patient thiamine or a
thiamine equivalent.
6. A method of treating myelofibrosis comprising administering to a
patient in need thereof a combination therapy comprising Compound
I, or a pharmaceutically acceptable salt or hydrate thereof, and
thiamine or a thiamine equivalent.
7. A method of mitigating thiamine deficiency comprising
administering Compound I, or a pharmaceutically acceptable salt or
hydrate thereof, to a patient at risk for developing thiamine
deficiency, wherein the patient is simultaneously exposed to
thiamine or a thiamine equivalent.
8. The method of any of claims 1-7, wherein the thiamine equivalent
is thiamine pyrophosphate.
9. A method for treating a patient comprising: (i) administering to
the patient Compound I, or a pharmaceutically acceptable salt or
hydrate thereof, (ii) analyzing the thiamine level in the patient,
and (iii) administering to the patient thiamine or a thiamine
equivalent if the patient's thiamine level is less than or equal to
about 30 nM/L.
10. The method of claim 9, wherein thiamine is administered to the
patient at an amount of about 100 mg per day.
11. The method of claim 10, wherein thiamine is administered
orally.
12. The method of claim 9, wherein thiamine is administered to the
patient at an amount of about 250 mg to about 500 mg.
13. The method of claim 12, wherein thiamine is administered to the
patient at an amount of about 250 mg.
14. The method of claim 12, wherein thiamine is administered to the
patient at an amount of about 500 mg.
15. The method of any of claims 12-14, wherein thiamine is
administered intravenously.
16. The method of claim 9, wherein thiamine is administered
according to the following schedule: about 500 mg TID for 2 or 3
days; about 250 mg to about 500 mg daily (QD) for 3-5 days; and
about 100 mg QD for 90 days.
17. The method of claim 9, wherein the patient is administered a
thiamine equivalent sufficient to deliver about 100 mg of thiamine
mg per day.
18. The method of claim 17, wherein the thiamine equivalent is
administered orally.
19. The method of claim 9, wherein the patient is administered a
thiamine equivalent sufficient to deliver about 250 mg to about 500
mg of thiamine.
20. The method of claim 19, wherein the thiamine equivalent is
sufficient to deliver about 250 mg of thiamine.
21. The method of claim 19, wherein the thiamine equivalent is
sufficient to deliver about 500 mg of thiamine.
22. The method of any of claims 19-21, wherein the thiamine
equivalent is administered intravenously.
23. The method of claim 17, wherein the thiamine equivalent is
sufficient to deliver an amount of thiamine according to the
following schedule: about 500 mg TID for 2 or 3 days; about 250 mg
to about 500 mg daily (QD) for 3-5 days; and about 100 mg QD for 90
days.
24. The method of any of claims 1-23, further comprising increasing
the patient's magnesium level.
25. The method of any of claims 1-24 wherein the patient has a
myeloproliferative disorder.
26. The method of claim 25, wherein the myeloproliferative disorder
is myelofibrosis.
27. The method of claim 26, wherein the myelofibrosis is primary
myelofibrosis.
28. The method of claim 27, wherein the primary myelofibrosis is
selected from intermediate risk primary myelofibrosis and high risk
primary myelofibrosis.
29. The method of claim 26, wherein the myelofibrosis is secondary
myelofibrosis.
30. The method of claim 26, wherein the myelofibrosis is post
essential thrombocythemia myelofibrosis.
31. The method of claim 26, wherein the myelofibrosis is post
polycythemia vera myelofibrosis.
32. The method of claim 25, wherein the myeloproliferative disorder
is acute myeloid leukemia (AML).
33. The method of claim 25, wherein the myeloproliferative disorder
is polycythemia vera.
34. The method of claim 25, wherein the myeloproliferative disorder
is essential thrombocythemia.
35. A method for treating a patient comprising: (i) administering
Compound I, or a pharmaceutically acceptable salt or hydrate
thereof, and (ii) conducting a cognitive assessment.
36. The method of claim 35, wherein the assessment occurs during
the 2.sup.nd 28-day cycle of Compound I administration.
37. The method of claim 35, wherein the assessment occurs during
the 3.sup.rd 28-day cycle of Compound I administration.
38. The method of claim 35, wherein the assessment occurs during at
least every 3.sup.rd 28-day cycle of Compound I administration.
39. The method of claim 35, wherein the assessment comprises a
mini-mental state examination.
40. The method of claim 35, further comprising analyzing the
thiamine level in the patient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. Provisional
Patent Application Nos. 62/736,369, filed on Sep. 25, 2018, and
62/783,076, filed on Dec. 20, 2018, their entireties of which are
hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention provides methods of treating,
stabilizing or lessening the severity or progression of a
myeloproliferative disorder.
BACKGROUND OF THE INVENTION
[0003] The search for new therapeutic agents has been greatly aided
in recent years by a better understanding of the structure of
enzymes and other biomolecules associated with diseases. One
important class of enzymes that has been the subject of extensive
study is protein kinases.
[0004] Protein kinases constitute a large family of structurally
related enzymes that are responsible for the control of a variety
of signal transduction processes within the cell. Protein kinases
are thought to have evolved from a common ancestral gene due to the
conservation of their structure and catalytic function. Almost all
kinases contain a similar 250-300 amino acid catalytic domain. The
kinases may be categorized into families by the substrates they
phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,
lipids, etc.).
[0005] In general, protein kinases mediate intracellular signaling
by effecting a phosphoryl transfer from a nucleoside triphosphate
to a protein acceptor that is involved in a signaling pathway.
These phosphorylation events act as molecular on/off switches that
can modulate or regulate the target protein biological function.
These phosphorylation events are ultimately triggered in response
to a variety of extracellular and other stimuli. Examples of such
stimuli include environmental and chemical stress signals (e.g.,
osmotic shock, heat shock, ultraviolet radiation, bacterial
endotoxin, and H.sub.2O.sub.2), cytokines (e.g., interleukin-1
(IL-1) and tumor necrosis factor .alpha. (TNF-.alpha.)), and growth
factors (e.g., granulocyte macrophage-colony-stimulating factor
(GM-CSF), and fibroblast growth factor (FGF)). An extracellular
stimulus may affect one or more cellular responses related to cell
growth, migration, differentiation, secretion of hormones,
activation of transcription factors, muscle contraction, glucose
metabolism, control of protein synthesis, and regulation of the
cell cycle.
[0006] Many diseases are associated with abnormal cellular
responses triggered by protein kinase-mediated events as described
above. These diseases include, but are not limited to, autoimmune
diseases, inflammatory diseases, bone diseases, metabolic diseases,
neurological and neurodegenerative diseases, cancer, cardiovascular
diseases, allergies and asthma, Alzheimer's disease, and
hormone-related diseases. Accordingly, there remains a need to find
protein kinase inhibitors useful as therapeutic agents.
SUMMARY OF THE INVENTION
[0007] The present disclosure provides methods of treating,
stabilizing or lessening the severity or progression of one or more
myeloproliferative disorders. In certain embodiments, provided
methods comprise mitigating one or more adverse events associated
with treatment of a myeloproliferative disorder. In some such
embodiments, the one or more adverse event is a thiamine
deficiency.
[0008] In some aspects, the present disclosure provides methods of
treating, stabilizing or lessening the severity or progression of
one or more myeloproliferative disorders comprising administering
to a patient a pharmaceutically acceptable composition comprising a
compound of formula I:
##STR00001##
or a pharmaceutically acceptable salt or hydrate thereof. The
compound of formula I is also referred to herein as "Compound I".
In some embodiments, Compound I is in the form of a dihydrochloride
salt. Compound I, or a pharmaceutically acceptable salt thereof,
may also exist in a hydrate form. In some such embodiments,
Compound I is in the form of a dihydrochloride monohydrate.
Accordingly, in some embodiments, provided methods comprise
administering to a patient in need thereof Compound II:
##STR00002##
[0009] In some embodiments, the present disclosure provides a
method of treating a myeloproliferative disorder, comprising [0010]
(i) administering to a patient in need thereof Compound I, or a
pharmaceutically acceptable salt or hydrate thereof, (e.g.,
Compound II); and [0011] (ii) monitoring the patient's thiamine
levels; [0012] wherein the patient's thiamine levels are adjusted
if the level of thiamine is below a reference standard.
[0013] In some embodiments, the patient's thiamine levels are
adjusted if the thiamine levels are about 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, or more below a reference standard. In some
embodiments, a reference standard is the patient's baseline level
of thiamine prior to administration of Compound I. In some
embodiments, a reference standard is a thiamine level that is from
about 74 nM/L to about 222 nM/L of whole blood.
[0014] In some embodiments, the patient is at risk for developing
Wernicke's encephalopathy.
[0015] In some embodiments, the patient's thiamine levels are
assessed by analyzing one or more biomarkers for thiamine
deficiency. In some embodiments, a biomarker for thiamine
deficiency is a serum thiamine level.
[0016] In some embodiments, the patient's thiamine levels are
adjusted by administering thiamine or a thiamine equivalent to the
patient.
[0017] In some embodiments, the present disclosure provides a
method for treating a patient comprising: [0018] (i) administering
to the patient Compound I, or a pharmaceutically acceptable salt or
hydrate thereof, (e.g., Compound II); [0019] (ii) analyzing the
thiamine level in the patient; and [0020] (iii) administering to
the patient thiamine or a thiamine equivalent if the patient's
thiamine level is less than about 74 nM/L to about 222 nM/L of
whole blood but greater than about 30 nM/L of whole blood.
[0021] In some embodiments, the patient is administered 100 mg
thiamine per day. In some embodiments, the patient is administered
a thiamine equivalent sufficient to deliver about 100 mg of
thiamine per day. In some such embodiments, the thiamine or
thiamine equivalent is administered orally.
[0022] In some embodiments, the present disclosure provides a
method for treating a patient comprising: [0023] (i) administering
to the patient Compound I, or a pharmaceutically acceptable salt or
hydrate thereof, (e.g., Compound II); [0024] (ii) analyzing the
thiamine level in the patient; and [0025] (iii) administering to
the patient thiamine or a thiamine equivalent if the patient's
thiamine level is less than or equal to about 30 nM/L of whole
blood.
[0026] In some embodiments, the thiamine or thiamine equivalent is
administered intravenously. In some embodiments, thiamine is
administered to the patient at an amount of about 250 mg. In some
embodiments, thiamine is administered to the patient at an amount
of about 250 mg per day (QD). In some embodiments, the patient is
administered a thiamine equivalent sufficient to deliver about 250
mg of thiamine per day.
[0027] In some embodiments, thiamine is administered to the patient
at an amount of about 500 mg. In some embodiments, thiamine is
administered to the patient at an amount of about 500 mg per day
(QD). In some embodiments, the patient is administered a thiamine
equivalent sufficient to deliver about 500 mg of thiamine QD. In
some embodiments, thiamine is administered to the patient at an
amount of about 500 mg three times daily (TID). In some
embodiments, the patient is administered a thiamine equivalent
sufficient to deliver about 500 mg of thiamine TID.
[0028] In some embodiments, thiamine is administered to the patient
at an amount of about 500 mg TID for 2 or 3 days, followed by
administration of thiamine at an amount of about 250 mg to about
500 mg daily (QD) for 3-5 days, followed by administration of
thiamine at an amount of about 100 mg QD for 90 days.
[0029] In some embodiments, provided methods further comprise
increasing the patient's magnesium level.
[0030] In some embodiments, the patient has a myeloproliferative
disorder. In some such embodiments, the myeloproliferative disorder
is myelofibrosis. In some embodiments, the myelofibrosis is primary
myelofibrosis. In some embodiments, the primary myelofibrosis is
Dynamic International Prognostic Scoring System (DIPSS)
intermediate or high-risk primary myelofibrosis. In some
embodiments, the myelofibrosis is secondary myelofibrosis. In some
embodiments, the myelofibrosis is post-essential thrombocythemia
myelofibrosis. In some embodiments, the myelofibrosis is
post-polycythemia vera myelofibrosis. In some embodiments, the
myeloproliferative disorder is polycythemia vera. In some
embodiments, the myeloproliferative disorder is essential
thrombocythemia. In some embodiments, the myeloproliferative
disorder is acute myeloid leukemia (AML).
[0031] In some embodiments, the present disclosure provides a
method for treating a patient comprising: [0032] (i) administering
Compound I, or a pharmaceutically acceptable salt or hydrate
thereof, (e.g., Compound II), and [0033] (ii) conducting a
cognitive assessment.
[0034] In some embodiments, the cognitive assessment occurs during
the 2.sup.nd 28-day cycle. In some embodiments, the cognitive
assessment occurs during the 3.sup.rd 28-day cycle. In some
embodiments, the cognitive assessment occurs during at least every
3.sup.rd 28-day cycle. In some embodiments, the cognitive
assessment comprises a mini-mental state examination. In some
embodiments, the method further comprises analyzing thiamine level
in the patient.
Definitions
[0035] The term "about" as used herein when referring to a
measurable value such as a parameter, an amount, a temporal
duration, and the like, is meant to encompass variations of +/-10%
or less, preferably +/-5% or less, more preferably +/-1% or less,
and still more preferably +/-0.1% or less of and from the specified
value, insofar such variations are appropriate to perform in the
disclosed invention. As an example, when the term "about" is used
in combination with a certain number of days, it includes said
specific number of days plus or minus 1 day, e.g., "about 6 days"
includes any number of days between 5 and 7. It is to be understood
that the value to which the modifier "about" refers is itself also
specifically, and preferably, disclosed.
[0036] The term "biomarker" is used herein to refer to a to an
entity, event, or characteristic whose presence, level, degree,
type, and/or form, correlates with a particular biological event or
state of interest, so that it is considered to be a "marker" of
that event or state. To give but a few examples, in some
embodiments, a biomarker may be or comprise a marker for a
particular disease state, or for likelihood that a particular
disease, disorder or condition may develop, occur, or reoccur. In
some embodiments, a biomarker may be or comprise a marker for a
particular disease or therapeutic outcome, or likelihood thereof.
Thus, in some embodiments, a biomarker is predictive, in some
embodiments, a biomarker is prognostic, in some embodiments, a
biomarker is diagnostic, of the relevant biological event or state
of interest. A biomarker may be or comprise an entity of any
chemical class, and may be or comprise a combination of entities.
For example, in some embodiments, a biomarker may be or comprise a
nucleic acid, a polypeptide, a lipid, a carbohydrate, a small
molecule, an inorganic agent (e.g., a metal or ion), or a
combination thereof. In some embodiments, a biomarker is a cell
surface marker. In some embodiments, a biomarker is intracellular.
In some embodiments, a biomarker is detected outside of cells
(e.g., is secreted or is otherwise generated or present outside of
cells, e.g., in a body fluid such as blood, urine, tears, saliva,
cerebrospinal fluid, etc. In some embodiments, a biomarker may be
or comprise a genetic or epigenetic signature. In some embodiments,
a biomarker may be or comprise a gene expression signature.
[0037] As used herein, the term "combination therapy" refers to
situations in which a subject is simultaneously exposed to two or
more therapeutic regimens (e.g., two or more therapeutic agents,
including one or more compounds as described herein). The two or
more regimens may be administered simultaneously or sequentially
(e.g., all doses of a first regimen are administered prior to
administration of any doses of a second regimen). In other
embodiments, such compounds are administered in overlapping dosing
regimens. "Administration" of a combination therapy may involve
administration of one or more compounds to a subject receiving the
other compound(s) in the combination. For clarity, combination
therapy does not require that individual compounds be administered
together in a single composition (or even necessarily at the same
time or by the same route of administration), although in some
embodiments, two or more compounds may be administered together in
a combination composition, or even in a combination compound (e.g.,
as part of a single chemical complex or covalent entity).
[0038] The term "thiamine equivalent" refers to an agent that
delivers or is capable of delivering a bioequivalent amount of
thiamine. Such thiamine equivalents include prodrugs of thiamine as
well as derivatives of thiamine such as thiamine monophosphate,
thiamine pyrophosphate (also known as thiamine diphosphate), and
thiamine triphosphate. In some embodiments, a thiamine equivalent
is a dietary form of thiamine such as that found in vegetables or
other food sources.
[0039] The terms "treat" or "treating," as used herein, refers to
partially or completely alleviating, inhibiting, delaying onset of,
preventing, ameliorating and/or relieving a disorder or condition,
or one or more symptoms of the disorder or condition. As used
herein, the terms "treatment," "treat," and "treating" refer to
partially or completely alleviating, inhibiting, delaying onset of,
preventing, ameliorating and/or relieving a disorder or condition,
or one or more symptoms of the disorder or condition, as described
herein. In some embodiments, treatment may be administered after
one or more symptoms have developed. In some embodiments, the term
"treating" includes preventing or halting the progression of a
disease or disorder. In other embodiments, treatment may be
administered in the absence of symptoms. For example, treatment may
be administered to a susceptible individual prior to the onset of
symptoms (e.g., in light of a history of symptoms and/or in light
of genetic or other susceptibility factors). Treatment may also be
continued after symptoms have resolved, for example to prevent or
delay their recurrence. Thus, in some embodiments, the term
"treating" includes preventing relapse or recurrence of a disease
or disorder.
[0040] The expression "unit dosage form" as used herein refers to a
physically discrete unit of inventive formulation appropriate for
the subject to be treated. It will be understood, however, that the
total daily usage of the compositions of the present invention will
be decided by the attending physician within the scope of sound
medical judgment. The specific effective dose level for any
particular subject or organism will depend upon a variety of
factors including the disorder being treated and the severity of
the disorder; activity of specific active agent employed; specific
composition employed; age, body weight, general health, sex and
diet of the subject; time of administration, and rate of excretion
of the specific active agent employed; duration of the treatment;
drugs and/or additional therapies used in combination or
coincidental with specific compound(s) employed, and like factors
well known in the medical arts.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0041] Myelofibrosis
[0042] Myeloproliferative neoplasm (MPN)-associated myelofibrosis
(MF) is a serious and life-threatening disease that can present as
a de novo or primary myelofibrosis (PMF) or evolve from previous
polycythemia vera (post PV-MF) or essential thrombocythemia (post
ET-MF) (Swerdlow S H, Campo E, Harris N L, Jafie E S, Pileri S A,
Stein H, et al. World Health Organization classification of tumors
of haematopoietic and lymphoid tissues. Lyon: IARC Press 2008). The
disease is characterized by clonal myeloproliferation, ineffective
erythropoiesis, bone marrow stromal changes, hepatosplenic
extramedullary hematopoiesis, and aberrant cytokine expression
(Tefferi A, Pardanani A. JAK inhibitors in myeloproliferative
neoplasms: rationale, current data and perspective. Blood Rev. 2011
September; 25(5):229-37). Patients typically present with
splenomegaly, constitutional symptoms, moderate to severe anemia,
thrombocytopenia, and leukocytosis.
[0043] Primary myelofibrosis is a member of a group of Philadelphia
chromosome (Ph1)-negative MPN which also includes PV and ET
(Tefferi A. The recent advances in classic BCR-ABL-negative
myeloproliferative disorders. Clin Adv Hematol Oncol. 2007a;
5:113-5). Almost all patients with PV and about one-half of
patients with ET and PMF have a JAK2 mutation, typically JAK2V617F.
Other mutations in patients with PMF include CALR and MPL. About
20% of patients with PMF have no detectable mutation in JAK2, CALR,
or MPL and are termed triple negative (Levine R L, Wadleigh M,
Cools J, Ebert B L, Wernig G, Huntly B J, et al. Activating
mutation in the tyrosine kinase JAK2 in polycythemia vera,
essential thrombocythemia, and myeloid metaplasia with
myelofibrosis. Cancer Cell. 2005; 7:387-97; Werning G, Mercher T,
Okabe R, Levine L, Lee B H, Gilliland GL. Expression of JAK2V617F
causes a polycythemia vera-like disease with associated
myelofibrosis in a murine bone marrow transplant model. Blood.
2006; 107:4274-81). Mutations in JAK2, CALR, and MPL result in
activation of the JAK/STAT signaling pathway resulting in cell
proliferation and inhibiting cell death. The result is clonal
expansion (Ilhe J N, Gilliland D G. JAK2: normal function and role
in hematopoietic disorders. Curr Opin Genet Dev. 2007; 17:8-14).
Thus, a JAK2 inhibitor that can down regulate the JAK/STAT pathway
is expected to be helpful in reducing cell proliferation.
[0044] Polycythemia vera (PV) and essential thrombocythemia (ET)
are characterized by increased levels of red blood cells (RBC) and
platelets. However, about 10% of affected patients develop bone
marrow fibrosis morphologically indistinguishable from PMF. These
conditions are termed post-PV-MF and post-ET-MF (Campbell P J,
Green A R. Management of polycythemia vera and essential
thrombocythemia. Hematology Am Soc Hematol Educ Program. 2005;
201-8), and are clinically named MPN associated myelofibrosis.
Patients with MPN-associated myelofibrosis have similar survival
prognoses to that of the PMF and about a 10% cumulative risk of
transformation to acute myeloid leukemia (AML).
[0045] There are several prognostic scoring systems predicting
survival of patients with PMF. The International Prognostic Scoring
System (IPSS) is used to predict survival at diagnosis and the
Dynamic International Prognostic Scoring System (DIPSS) at any time
in the disease course (Cervantes F, Dupriez B, Pereira A, et al.
New prognostic scoring system for primary myelofibrosis based on a
study of the International Working Group for Myelofibrosis Research
and Treatment. Blood. 2009; Mar. 26; 113(13):2895-901; Passamonti
F, Cervantes F, Vannucchi A M, Morra E, Rumi E, Pereira A, et al. A
dynamic prognostic model to predict survival in primary
myelofibrosis: a study by the IWG-MRT (International Working Group
for Myeloproliferative Neoplasms Research and Treatment). Blood.
2010 Mar. 4; 115(9):1703-8). Variables included in the IPSS are age
>65 years, constitutional symptoms, hemoglobin level <10
g/dL, and white blood cell (WBC) counts. Additional recent
prognostic scoring systems include the Dynamic International
Prognostic Scoring System Plus (DIPSS Plus) and scoring systems
incorporating data from mutation analyses. There is a strong
association between overall survival for MF patients and the DIPSS
risk category for patients with low, intermediate risk 1,
intermediate risk 2, or high risk with median survival of 15.4,
6.5, 2.9, and 1.3 years, respectively (Tefferi A. Primary
myelofibrosis: 2017 update on diagnosis, risk-stratification, and
management. Am J Hematol. 2016 December; 91(12):1262-1271).
[0046] Approximately 70% of individuals with MF are in the
intermediate-2 or high-risk categories (Gangat N, Caramazza D,
Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a
refined Dynamic International Prognostic Scoring System for primary
myelofibrosis that incorporates prognostic information from
karyotype, platelet count, and transfusion status. J Clin Oncol.
2011 Feb. 1; 29(4):392-7), representing the greatest unmet medical
need. Symptomatic enlargement of the spleen and liver, the
necessity for RBC transfusions, cachexia, and the other
MF-associated symptoms result in greatly compromised quality of
life in these patients (Mesa R A, Camoriano J K, Geyer S M, Wu W,
Kaufmann S H, Rivera C E, et al. A phase II trial of tipifarnib in
myelofibrosis: primary, post-polycythemia vera and post-essential
thrombocythemia. Leukemia. 2007 September; 21(9):1964-70).
[0047] Compound I
[0048] The synthesis of the Compound I is disclosed in Example 90
of U.S. Pat. No. 7,528,143, issued May 5, 2009, which is hereby
incorporated by reference in its entirety. Compound I, also known
as fedratinib, is a potent and selective inhibitor of JAK2 kinase
activity that in cellular assays inhibits JAK2 signaling, cellular
proliferation driven by mutant JAK2 or mutant MPL, and induces
apoptosis in cells expressing constitutively active JAK2. Compound
I also inhibits erythroid colony formation of hematopoietic
progenitors isolated from myeloproliferative neoplasm (MPN)
patients.
[0049] Myelofibrosis (MF) is a clonal disease resulting from
mutations in CD34+ hematopoietic stem cells that promote abnormal
proliferation and myeloid differentiation (Mead A J, 2017). In
addition to JAK2V617F, several other mutations, in JAK2 and other
genes, are found in MF patients and have been associated with
prognosis, AML progression, and response to the JAK inhibitor
ruxolitinib (Vainchenker W, Kralovics R. Genetic basis and
molecular pathophysiology of classical myeloproliferative
neoplasms. Blood. 2017 Feb. 9; 129(6):667-679, Tefferi A,
Guglielmelli P, Nicolosi M, Mannelli F, et al. GIPSS: genetically
inspired prognostic scoring system for primary myelofibrosis.
Leukemia. 2018 Mar. 23; Spiegel J Y, McNamara C, Kennedy J A,
Panzarella T, et al. Impact of genomic alterations on outcomes in
myelofibrosis patients undergoing JAK1/2 inhibitor therapy. Blood.
2017 Sep. 8; 1(20):1729-1738; Newberry K J, Patel K, Masarova L,
Luthra R, et al. Clonal evolution and outcomes in myelofibrosis
after ruxolitinib discontinuation. Blood. 2017 Aug. 31;
130(9):1125-1131; Patel K P, Newberry K J, Luthra R, Jabbour E, et
al. Correlation of mutation profile and response in patients with
myelofibrosis treated with ruxolitinib. Blood. 2015 Aug. 6;
126(6):790-7; Levine R L, Wadleigh M, Cools J, Ebert B L, Wernig G,
Huntly B J, et al. Activating mutation in the tyrosine kinase JAK2
in polycythemia vera, essential thrombocythemia, and myeloid
metaplasia with myelofibrosis. Cancer Cell. 2005; 7:387-97; Werning
G, Mercher T, Okabe R, Levine L, Lee B H, Gilliland G L. Expression
of JAK2V617F causes a polycythemia vera-like disease with
associated myelofibrosis in a murine bone marrow transplant model.
Blood. 2006; 107:4274-81; Mercher T, Wernig G, Moore S A, Levine R
L, Gu T L, Frohling S, Cullen D, Polakiewicz R D, Bernard O A,
Boggon T J, Lee B H, Gilliland D G. JAK2T875N is a novel activating
mutation that results in myeloproliferative disease with features
of megakaryoblastic leukemia in a murine bone marrow
transplantation model. Blood. 2006 Oct. 15; 108(8):2770-9; Scott L
M, Tong W, Levine R L, Scott M A, Beer P A, Stratton M R, et al.
JAK2 exon 12 mutations in polycythemia vera and idiopathic
erythrocytosis. N Engl J Med. 2007 Feb. 1; 356(5):459-68; Pardanani
A, Tefferi A, Jamieson C, Gabrail N Y, et al. A phase 2 randomized
dose-ranging study of the JAK2-selective inhibitor fedratinib
(SAR302503) in patients with myelofibrosis. Blood Cancer J. 2015
Aug. 7; 5:e335).
[0050] Phosphorylated STAT3 (pSTAT3) is a downstream effector of
activated JAK2. Tracking pSTAT3 level in circulating cells has
proven a useful pharmacodynamics (PD) biomarker of fedratinib-JAK2
engagement in MF patients (Pardanani A, Tefferi A, Jamieson C,
Gabrail N Y, et al. A phase 2 randomized dose-ranging study of the
JAK2-selective inhibitor fedratinib (SAR302503) in patients with
myelofibrosis. Blood Cancer J. 2015 Aug. 7; 5:e335). Preclinical
data indicates that fedratinib is also able to inhibit pSTAT5; and
basal levels of pSTAT5 in AML cells have been reported to predict
response to fedratinib in AML xenograft models (Chen W C, Yuan J S,
Xing Y, Mitchell A, Mbong N, et al. An Integrated Analysis of
Heterogeneous Drug Responses in Acute Myeloid Leukemia That Enables
the Discovery of Predictive Biomarkers. Cancer Res. 2016 Mar. 1;
76(5):1214-24). Abnormal cytokine expression and bone marrow
fibrosis are hallmarks of MF (Vainchenker W, Kralovics R. Genetic
basis and molecular pathophysiology of classical myeloproliferative
neoplasms. Blood. 2017 Feb. 9; 129(6):667-679; Mondet J, Hussein K,
Mossuz P. Circulating Cytokine Levels as Markers of Inflammation in
Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and
Prognostic Interest. Mediators Inflamm. 2015; 2015:670580). High
levels of pro-inflammatory and fibrogenic cytokines have been
reported to contribute to bone marrow (BM) stromal changes,
ineffective erythropoiesis/extramedullary hematopoiesis and
constitutional symptoms in MF (Mondet J, Hussein K, Mossuz P.
Circulating Cytokine Levels as Markers of Inflammation in
Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and
Prognostic Interest. Mediators Inflamm. 2015; 2015:670580; Tefferi
A, Pardanani A. JAK inhibitors in myeloproliferative neoplasms:
rationale, current data and perspective. Blood Rev. 2011 September;
25(5):229-37). Fedratinib was found to modulate circulating
cytokines in MF patients not previously treated with JAK inhibitors
(Pardanani A, Tefferi A, Jamieson C, Gabrail N Y, et al. A phase 2
randomized dose-ranging study of the JAK2-selective inhibitor
fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer
J. 2015 Aug. 7; 5:e335). Cytokine modulation correlated with
sustained viral response (SVR) and improvement in constitutional
symptoms in these patients (Pardanani A, Tefferi A, Jamieson C,
Gabrail N Y, et al. A phase 2 randomized dose-ranging study of the
JAK2-selective inhibitor fedratinib (SAR302503) in patients with
myelofibrosis. Blood Cancer J. 2015 Aug. 7; 5:e335).
[0051] Recent studies are starting to unveil immune regulatory
roles for JAK2V617F, as well as for JAK inhibitors like
ruxolitinib. For instance, JAK2V617F was found to contribute to
immune evasion of MPN myeloid cells by upregulation of program
death-ligand 1 (PD-L1) (Prestipino A, Emhardt A J, Aumann K,
O'Sullivan D, et. al. Oncogenic JAK2V617F causes PD-L1 expression,
mediating immune escape in myeloproliferative neoplasms. Sci Transl
Med. 2018 Feb. 21; 10(429)), and ruxolitinib has been reported to
modulate PD-L1 expression in these cells (Prestipino A, Emhardt A
J, Aumann K, O'Sullivan D, et. al. Oncogenic JAK2V617F causes PD-L1
expression, mediating immune escape in myeloproliferative
neoplasms. Sci Transl Med. 2018 Feb. 21; 10(429)). However,
preclinical and clinical data indicate that ruxolitinib is also a
potent immunosuppressive drug, which can suppress graft-versus-host
disease (GVHD), decrease frequency and impair activation of T- and
NK-cells of MF patients (Betts B C, Bastian D, Iamsawat S, Nguyen
H, et al. Targeting JAK2 reduces GVHD and xenograft rejection
through regulation of T cell differentiation. Proc Natl Acad Sci
USA. 2018 Feb. 13; 115(7):1582-1587. Epub 2018; Schonberg K,
Rudolph J, Vonnahme M, Parampalli et al. Cancer JAK Inhibition
Impairs NK Cell Function in Myeloproliferative Neoplasms. Res. 2015
Jun. 1; 75(11):2187-99; Parampalli Yajnanarayana S, Stubig T,
Cornez I, Alchalby H, et al. JAK1/2 inhibition impairs T cell
function in vitro and in patients with myeloproliferative
neoplasms. Br J Haematol. 2015 June; 169(6):824-33). Preclinical
data suggest that fedratinib is able to modulate PD-L1 expression
in lymphoma tumor cells (Hao Y, Chapuy B, Monti S, Sun H H, Rodig S
J, Shipp M A. Selective JAK2 inhibition specifically decreases
Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in
vitro and in vivo. Clin Cancer Res. 2014 May 15; 20(10):2674-83),
however, it is neither a potent suppressor of GVHD, nor able to
impair human T cell development in xenograft mouse models (Betts B
C, Veerapathran A, Pidala J, Yang H, et al. Targeting Aurora kinase
A and JAK2 prevents GVHD while maintaining Treg and antitumor CTL
function. Sci Transl Med. 2017 Jan. 11; 9(372)). The selective
activity of fedratinib on JAK2 raises the possibility that
fedratinib might have immune-modulatory effects without impairing
T- or NK-cell function in MF patients.
[0052] In some embodiments, the present disclosure provides a
method for preventing and/or mitigating thiamine deficiency in a
patient receiving Compound I, or a pharmaceutically acceptable salt
or hydrate thereof, (e.g., Compound II). In some embodiments, the
present disclosure provides a method for treating a patient
comprising administering Compound I, or a pharmaceutically
acceptable salt or hydrate thereof, (e.g., Compound II), and
monitoring the thiamine levels in the patient.
[0053] In some embodiments, the present disclosure provides a
method of treating a myeloproliferative disorder, comprising [0054]
(i) administering to a patient in need thereof a JAK1 and/or JAK2
inhibitor; and [0055] (ii) monitoring the patient's thiamine
levels.
[0056] In some such embodiments, the method further comprises
adjusting the patient's thiamine levels if the level of thiamine is
below a reference standard (e.g., baseline level). In some
embodiments, the JAK1 and/or JAK2 inhibitor is Compound I, or a
pharmaceutically acceptable salt thereof, (e.g., Compound II).
[0057] Accordingly, in some embodiments, the present disclosure
provides a method of treating a myeloproliferative disorder,
comprising [0058] (i) administering to a patient in need thereof
Compound I, or a pharmaceutically acceptable salt or hydrate
thereof, (e.g., Compound II); and [0059] (ii) monitoring the
patient's thiamine levels; [0060] wherein the patient's thiamine
levels are adjusted if the level of thiamine is below a reference
standard.
[0061] In some embodiments, the patient's thiamine levels are
assessed by analyzing one or more biomarkers for thiamine
deficiency. In some embodiments, a biomarker for thiamine
deficiency is a serum thiamine level.
[0062] In some embodiments, the level of the biomarker is compared
to a reference standard. In some embodiments, the reference
standard is a baseline level of the biomarker (e.g., the level of
the biomarker prior to administration of Compound I or Compound
II). In some embodiments, the reference standard is a level of the
biomarker that is considered to be within a range typically
observed in a healthy population (e.g., a population that is not
afflicted with the target disease or disorder). In some
embodiments, the reference standard is a level of the biomarker
that is considered to be within a range typically observed in a
population that has been diagnosed with the target disease or
disorder.
[0063] In some embodiments, the level of the biomarker following
administration of Compound I or Compound II is lower than the
reference standard (e.g., lower than the baseline level of the
biomarker).
[0064] In some embodiments, the patient's thiamine levels are
adjusted if the thiamine levels are about 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, or more below a reference standard. In some
embodiments, a reference standard is the patient's baseline level
of thiamine prior to administration of Compound I or Compound II.
In some embodiments, a reference standard is a thiamine level that
is from about 74 nM/L to about 222 nM/L of whole blood.
[0065] In some embodiments, the patient is at risk for developing
Wernicke's encephalopathy.
[0066] In some embodiments, the patient's thiamine levels are
adjusted by administering thiamine or a thiamine equivalent to the
patient.
[0067] In some embodiments, the present disclosure provides a
method for treating a patient comprising: [0068] (i) administering
to the patient Compound I, or a pharmaceutically acceptable salt or
hydrate thereof, (e.g., Compound II), [0069] (ii) analyzing the
thiamine level in the patient, and [0070] (iii) administering to
the patient thiamine or a thiamine equivalent if the patient's
thiamine level is less than or equal to about 30 nM/L of whole
blood.
[0071] In some embodiments, the present disclosure provides a
method of mitigating thiamine deficiency, the method comprising
administering Compound I, or a pharmaceutically acceptable salt or
hydrate thereof, (e.g., Compound II), to a patient at risk for
developing thiamine deficiency, wherein the patient is
simultaneously exposed to thiamine or a thiamine equivalent.
[0072] In some such embodiments, the patient is administered about
100 mg thiamine per day. In some embodiments, the patient is
administered a thiamine equivalent sufficient to deliver about 100
mg of thiamine per day. In some embodiments, the thiamine or
thiamine equivalent is administered orally.
[0073] In some embodiments, the patient is administered a thiamine
equivalent that delivers about 100 mg thiamine per day.
[0074] In some embodiments, the present disclosure provides a
combination therapy comprising (i) Compound I, or a
pharmaceutically acceptable salt or hydrate thereof, (e.g.,
Compound II), and (ii) thiamine or a thiamine equivalent.
[0075] In some embodiments, the present disclosure provides a
method of treating myelofibrosis comprising administering to a
patient in need thereof a combination therapy comprising Compound
I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g.,
Compound II), and thiamine or a thiamine equivalent. In some such
embodiments, thiamine is administered in an amount of about 100 mg
per day (QD). In some embodiments, the patient is administered a
thiamine equivalent sufficient to deliver about 100 mg of thiamine
per day. In some embodiments, the thiamine or thiamine equivalent
is administered orally.
[0076] In some such embodiments, thiamine is administered in an
amount of about 500 mg thiamine TID. In some such embodiments, the
patient is administered about 250 or about 500 mg thiamine QD. In
some embodiments, the patient is administered a thiamine equivalent
sufficient to deliver about 250 mg or about 500 mg thiamine per day
(QD). In some embodiments, the about 250 mg or about 500 mg
thiamine is administered orally. In some embodiments, the thiamine
equivalent is administered orally.
[0077] In some embodiments, a thiamine equivalent is thiamine
pyrophosphate.
[0078] In some embodiments, provided methods further comprise
increasing the patient's magnesium level. In some embodiments, the
patient's magnesium level is increased by administering a magnesium
supplement.
[0079] In some embodiments, the patient has a myeloproliferative
disorder.
[0080] In some embodiments, the myeloproliferative disorder is
myelofibrosis. In some embodiments, the myelofibrosis is primary
myelofibrosis. In some embodiments, the myelofibrosis is secondary
myelofibrosis. In some embodiments, the myelofibrosis is
post-essential thrombocythemia myelofibrosis. In some embodiments,
the myelofibrosis is post-polycythemia vera myelofibrosis.
[0081] In some embodiments, the myeloproliferative disorder is
polycythemia vera. In some embodiments, the myeloproliferative
disorder is essential thrombocythemia. In some embodiments, the
myeloproliferative disorder is acute myeloid leukemia.
[0082] In some embodiments, Compound I is administered in the form
of a dihydrochloride monohydrate (e.g., Compound II).
[0083] In some embodiments, Compound I, or a pharmaceutically
acceptable salt or hydrate thereof, (e.g., Compound II), is
administered to the patient in a unit dosage form. In some
embodiments, the unit dosage form of Compound I or Compound II is
based on the free base weight of the compound. For example, a 100
mg dose of the free base form of Compound I equates to about 117.30
mg of Compound I in its dihydrochloride monohydrate form (i.e.,
Compound II). In some embodiments, the unit dosage form of Compound
I or Compound II is about 50 mg, about 100 mg, about 150 mg, or
about 200 mg, based on the free base weight of the compound. In
some embodiments, the unit dosage form of Compound I or Compound II
is 100 mg, based on the free base weight of the compound.
[0084] In some embodiments, Compound I, or a pharmaceutically
acceptable salt or hydrate thereof, (e.g., Compound II), is
administered in an oral dosage form. In some such embodiments, the
oral dosage form is a capsule. In some embodiments, the oral dosage
form is a tablet.
[0085] In some embodiments, Compound I, or a pharmaceutically
acceptable salt or hydrate thereof, (e.g., Compound II), is
administered once daily (QD). In some embodiments, Compound I, or a
pharmaceutically acceptable salt or hydrate thereof, (e.g.,
Compound II), is administered at a total daily dose of about 200
mg, about 300 mg or about 400 mg. In some embodiments, Compound I
or Compound II is administered to the patient at a total daily dose
of about 400 mg. In some embodiments, Compound I or Compound II is
administered to the patient at a total daily dose of about 300 mg.
In some embodiments, Compound I or Compound II is administered to
the patient at a total daily dose of about 200 mg. In some
embodiments, the total daily dose of Compound I or Compound II is
modified due to an adverse event. In some embodiments, the total
daily dose of Compound I or Compound II is reduced. In some
embodiments, the total daily dose of Compound I or Compound II is
reduced from about 400 mg to about 300 mg. In some embodiments, the
total daily dose of Compound I or Compound II is reduced to about
200 mg.
[0086] In some embodiments, Compound I, or a pharmaceutically
acceptable salt or hydrate thereof, (e.g., Compound II), is
administered once daily for a 28 day cycle. In some embodiments,
Compound I, or a pharmaceutically acceptable salt or hydrate
thereof, (e.g., Compound II), is administered once daily for two
28-day cycles. In some embodiments, Compound I, or a
pharmaceutically acceptable salt or hydrate thereof, (e.g.,
Compound II), is administered once daily for three, four, five, or
more 28-day cycles. In some embodiments, Compound I, or a
pharmaceutically acceptable salt or hydrate thereof, (e.g.,
Compound II), is administered once daily for six, seven, eight,
nine, ten, eleven, twelve or more 28-day cycles. In some
embodiments, Compound I, or a pharmaceutically acceptable salt or
hydrate thereof, (e.g., Compound II), is administered once daily
until symptoms of disease are no longer measureable. In some
embodiments, Compound I or Compound II is administered for the
duration of a patient's life. In some embodiments, Compound I or
Compound II is administered once daily for one or more 28-day
cycles, followed by a dose holiday. A "dose holiday" as used herein
refers to a period of time wherein Compound I or Compound II is not
administered to the patient. In some embodiments, a dose holiday is
one day, one week, or one 28-day cycle. In some embodiments,
Compound I or Compound II is administered once daily for one or
more 28-day cycles, followed by a dose holiday, and then resumption
of administration of Compound I or Compound II once daily at the
same dose level prior to the dose holiday. In some embodiments,
Compound I or Compound II is administered once daily for one or
more 28-day cycles, followed by a dose holiday, and then resumption
of administration of Compound I or Compound II once daily at a dose
level that is 100 mg less than the dose of Compound I or Compound
II prior to the dose holiday. In some embodiments, the total daily
dose of Compound I or Compound II is titrated upward by 100 mg
following a prior dose reduction.
[0087] In some embodiments, provided methods comprise administering
Compound I, or a pharmaceutically acceptable salt or hydrate
thereof, (e.g., Compound II), once daily for two or more 28-day
cycles. In some such embodiments, the patient's thiamine levels are
assessed at the beginning of the 2.sup.nd 28-day cycle.
[0088] In some embodiments, provided methods comprise administering
Compound I, or a pharmaceutically acceptable salt or hydrate
thereof, (e.g., Compound II), once daily to the patient for two or
more 28-day cycles, wherein the patient's thiamine levels are
assessed at the beginning of every 28-day cycle. In some
embodiments, provided methods comprise administering Compound I, or
a pharmaceutically acceptable salt or hydrate thereof, (e.g.,
Compound II), once daily to the patient for two or more 28-day
cycles, wherein the patient's thiamine levels are assessed at the
end of each 28-day cycle. In some embodiments, provided methods
comprise administering Compound I, or a pharmaceutically acceptable
salt or hydrate thereof, (e.g., Compound II), once daily to the
patient for two or more 28-day cycles, wherein the patient's
thiamine levels are assessed at the beginning of the 2.sup.nd
28-day cycle and at the beginning of the 3.sup.rd 28-day cycle. In
some such embodiments, the patient's thiamine levels are assessed
every 3.sup.rd 28-day cycle thereafter. For example, if a patient
is treated for twelve 28-day cycles, thiamine levels are assessed
on day 1 (.+-.3 days) of each of the 2.sup.nd cycle, 3.sup.rd
cycle, 6.sup.th cycle, 9.sup.th cycle and 12.sup.th cycle. In some
embodiments, provided methods comprise administering Compound I, or
a pharmaceutically acceptable salt or hydrate thereof, (e.g.,
Compound II), once daily to the patient for six or more 28-day
cycles, wherein the patient's thiamine levels are assessed at the
beginning of each of the 1.sup.st cycle, 2.sup.nd cycle, 3.sup.rd
cycle, 4.sup.th cycle, 5.sup.th cycle and 6.sup.th cycle.
[0089] In some embodiments, provided methods comprise administering
thiamine or a thiamine equivalent to the patient when the patient's
thiamine levels are below normal (e.g., 74-222 nM/L of whole blood)
but greater than or equal to 30 nM/L of whole blood. In some such
embodiments, the thiamine or thiamine equivalent is administered
orally. In some embodiments, thiamine is administered to the
patient at a dose of about 100 mg per day. In some embodiments, the
patient is administered a thiamine equivalent sufficient to deliver
about 100 mg of thiamine per day.
[0090] In some embodiments, provided methods comprise administering
thiamine or a thiamine equivalent when the patient's thiamine
levels are 30 nM/L of whole blood. In some such embodiments, the
thiamine is administered to the patient according to the following
schedule: [0091] (i) about 500 mg three times daily (TID) for 2 or
3 days, [0092] (ii) about 250 mg to about 500 mg daily (QD) for 3
to 5 days, and [0093] (iii) about 100 mg daily (QD) for at least 90
days.
[0094] In some embodiments, a patient whose thiamine levels are 30
nM/L of whole blood is administered a thiamine equivalent
sufficient to deliver an amount of thiamine according to the
following schedule: [0095] (i) about 500 mg three times daily (TID)
for 2 or 3 days, [0096] (ii) about 250 mg to about 500 mg daily
(QD) for 3 to 5 days, and [0097] (iii) about 100 mg daily (QD) for
at least 90 days.
[0098] In some embodiments, thiamine or thiamine equivalent is
administered intravenously.
[0099] In some embodiments, provided methods further comprise
monitoring the patient's magnesium levels. In some such
embodiments, provided methods comprise increasing the patient's
magnesium level.
[0100] In some embodiments, the patient has a myeloproliferative
disease or condition. In some embodiments, the myeloproliferative
disease or condition is selected from primary myelofibrosis,
secondary myelofibrosis, polycythemia vera, essential
thrombocythemia, post polycythemia vera, and post essential
thrombocythemia. In some embodiments, the myeloproliferative
disorder is acute myeloid leukemia (AML). In some embodiments, the
primary myelofibrosis is Dynamic International Prognostic Scoring
System (DIPSS) intermediate or high-risk primary myelofibrosis. In
some embodiments, said method comprises administering to a patient
in need thereof a composition according to the present
invention.
[0101] In some embodiments, the present disclosure provides a
method for treating a patient comprising: [0102] (i) administering
Compound I, or a pharmaceutically acceptable salt or hydrate
thereof, (e.g., Compound II), and [0103] (ii) conducting a
cognitive assessment.
[0104] In some embodiments, the cognitive assessment occurs during
the 2.sup.nd 28-day cycle. In some embodiments, the cognitive
assessment occurs during the 3.sup.rd 28-day cycle. In some
embodiments, the cognitive assessment occurs during at least every
3.sup.rd 28-day cycle. In some embodiments, the cognitive
assessment comprises a mini-mental state examination. In some
embodiments, the method further comprises analyzing thiamine level
in the patient.
EXEMPLIFICATION
[0105] Protocol Summary. A multicenter, single-arm, open-label
efficacy and safety study of fedratinib in subjects previously
treated with ruxolitinib and with DIPSS (Dynamic International
Prognostic Scoring System) intermediate or high-risk primary
myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV
MF), or post-essential thrombocythemia myelofibrosis (post-ET
MF).
[0106] Objectives. The primary objective of the study is to
evaluate the percentage of subjects with at least a 35% spleen
volume reduction with fedratinib. The secondary objectives are:
[0107] To evaluate the safety of fedratinib [0108] To evaluate the
reduction of spleen size by palpation [0109] To evaluate
myelofibrosis (MF)-associated symptoms as measured by the
Myelofibrosis Symptom Assessment Form (MFSAF) [0110] To evaluate
duration of spleen response by MRI (magnetic resonance imaging)/CT
(computed tomography) and by palpation [0111] To evaluate the
duration of symptoms response [0112] To assess the effectiveness of
the risk mitigation strategy for gastrointestinal (GI) events
[0113] To assess the risk mitigation strategy for Wernicke's
encephalopathy (WE) The exploratory objectives are: [0114] To
evaluate Overall Survival (OS) [0115] To assess the effect of study
treatment on selected treatment-related symptoms from the subject's
perspective (diarrhea, nausea, vomiting, dizziness, headache),
assessed by the Patient Reported Outcome Version of the Common
Terminology Criteria for Adverse Events (PRO-CTCAE) [0116] To
explore prognostic markers (e.g., gene mutations, cytogenics) at
baseline and in relation to efficacy parameters [0117] To explore
biomarkers related to mechanisms of action of fedratinib (eg,
circulating cytokines)
[0118] Study Population. The study will enroll approximately 110
subjects with intermediate- or high-risk primary myelofibrosis
(PMF), post-polycythemia vera myelofibrosis (post-PV MF), or
post-essential thrombocythemia myelofibrosis (post-ET MF).
[0119] All subjects discontinued from protocol-prescribed therapy
for any reason will be followed for survival, subsequent therapies,
and progression of myelofibrosis to acute myeloid leukemia (AML)
every 3 months until death or up to 12 months after End of
Treatment (EOT), lost to follow-up, withdrawal of consent for
further data collection, or study closure, whichever comes
first.
[0120] Study Design. The study will consist of the following 3
phases: [0121] A 28-day Screening Period [0122] Fedratinib
Treatment Period including a 30-Day Follow-up After Last Dose Visit
[0123] A 12 month Survival Follow-up Period
[0124] Length of Study. The expected duration of study is
approximately 4 years, which includes approximately 18 months to
fully enroll, and 24 months for treatment and follow-up.
[0125] The End of Trial is defined as either the date of the last
visit of the last subject to complete the Survival Follow-up, or
the date of receipt of the last data point from the last subject
that is required for primary, secondary and/or exploratory
analysis, as prespecified in the protocol, whichever is the later
date.
[0126] Screening Period. All enrolled subjects will undergo
screening procedures during the screening period which must be
completed within 28 days prior to the start of study treatment.
This will serve to determine subject eligibility based on all
inclusion and exclusion criteria defined in the protocol. For
subjects that are receiving ruxolitinib during the screening period
or that have potentially reversible laboratory abnormalities (or
other criteria that excludes the subject from enrollment) detected
during screening, the screening period may be extended to 35 days
(additional 7 days).
[0127] Treatment Period. Upon confirmation of eligibility, subjects
will be enrolled and receive treatment with fedratinib at a dose of
400 mg once daily orally continuously. Fedratinib is administered
as the dihydrochloride monohydrate form (i.e., Compound II). Cycles
are defined for administrative purposes as 4-week (28-day) periods.
Unless otherwise noted, visit windows are .+-.3 days except for
MRI/CT scan procedures which have a visit window of .+-.7 days. For
the first 3 cycles, site visits will be performed on Day 1 and Day
15 and thereafter on Day 1 for the subsequent cycles. At Cycle 1
Day 8 the site will contact the subject by telephone to assess
occurrence and discuss management of nausea, vomiting and diarrhea.
Subjects may continue treatment with fedratinib until unacceptable
toxicity, lack of therapeutic effect or withdraws consent. All
subjects will be monitored for adverse events during the study. All
subjects discontinued from protocol prescribed therapy for any
reason will be followed for a period of 30 days following the last
dose of fedratinib.
[0128] Fedratinib is self-administered orally once daily
continuously on an outpatient basis, preferably together with food
at dinner in the evening, the same time each day. In case a dose is
missed, the next dose should be taken the following day at the same
time of day as previously taken before the dose was missed.
[0129] For the first 3 cycles, site visits will be performed on Day
1 and Day 15 and thereafter on Day 1 for the subsequent cycles. At
Cycle 1 Day 8 the site will contact the subject by telephone to
assess occurrence and discuss management of nausea, vomiting and
diarrhea.
[0130] Subjects may continue treatment with fedratinib until
unacceptable toxicity, lack of therapeutic effect, progression of
disease, or until consent is withdrawn.
[0131] All subjects will be monitored for adverse events during the
study.
[0132] All subjects discontinued from protocol-prescribed therapy
for any reason will be followed for at least a period of 30 days
following the last dose of fedratinib.
[0133] The most common adverse events associated with fedratinib
are hematological and gastrointestinal. Hematological adverse
events associated with JAK inhibitors are dose dependent,
mechanism-based and their managed through dose reductions, dose
interruptions and transfusions.
[0134] The fedratinib dose in this study is 400 mg/day. If a
subject experience a drug toxicity as specified in the Dose
Modification Schedule table (Table 1), the dosing should be
interrupted and the dose may need to be modified.
[0135] If a subject does not tolerate fedratinib therapy after 2
dose level reductions from the starting dose, he/she must be
withdrawn from the study treatment. If the toxicity does not
resolve in the time period as specified in the Dose Modification
Schedule table (Table 1), subjects must be withdrawn from the study
treatment. Reescalation of doses is possible in certain cases as
defined in the Dose Modification Schedule table (Table 1). The
daily dose of fedratinib cannot exceed 400 mg/day.
[0136] Subjects may continue treatment with fedratinib until
unacceptable toxicity, lack of therapeutic effect or until a
subject is not compliant with treatment or withdraws consent.
[0137] Dose Modification Schedule
[0138] A flexible dose modification regimen may be employed to
minimize drug toxicity for individual subjects, with possible daily
doses are of 200 mg, 300 mg, or 400 mg.
[0139] The most common adverse events associated with fedratinib
are hematological and gastrointestinal events. Hematological
adverse events associated with JAK inhibitors are dose dependent,
mechanism-based and are managed through dose reductions, dose
interruptions and transfusions.
[0140] If a subject experiences a drug toxicity as specified in
Table 1, infra, the dosing must be interrupted; in some cases (i.e.
when it is not a liver function test (LFT) abnormality) the dose
can be titrated by a 100 mg/day decrement during the study,
depending upon the Investigator's judgment, down to a minimum dose
of 200 mg/day. For subjects with severe impairment of renal
function and co-administration of strong or moderate CYP3A4
inhibitors the fedratinib dose is adjusted.
[0141] If a subject does not tolerate fedratinib therapy after 2
dose level reductions from the starting dose, he/she must be
withdrawn from the study treatment. If the toxicity does not
resolve in the time period as specified in Table 1, subjects must
be withdrawn from the study treatment. Reescalation of doses is
possible in certain cases. The daily dose of fedratinib cannot
exceed 400 mg/day (based on the free base weight).
TABLE-US-00001 TABLE 1 Dose Modification Schedule Fedratinib
Fedratinib Dose After Adverse Event Management Recovery Recovery
Hematological Grade 4 or Grade 3 Hold fedratinib up to Grade
.ltoreq.3 Dose decrement by 1 thrombocytopenia 28 days
thrombocytopenia dose level: 100 mg/daily with major bleeding
without bleeding decrease Grade 4 neutropenia Hold fedratinib up to
Grade .ltoreq.2 Dose decrement by 1 28 days neutropenia dose level:
100 mg/daily decrease Grade 4 -- Toxicity resolves Subsequent
upward dose hematological for at least 1 cycle titration possible
of 1 toxicity with dose dose level (100 mg daily) reduction in per
cycle as per the subsequent cycle Investigator's discretion
Recurrence of a grade -- -- Subsequent upward dose 4 hematological
titration not permitted toxicity Fedratinib discontinuation as per
the Investigator's discretion Non-hematological Drug-related non-
-- -- Subsequent upward dose hematological Grade titration not
permitted 4 or unmanageable Fedratinib Grade 3 toxicity with
discontinuation as per the dose reduction in Investigator's
discretion subsequent cycle Hepatic (LFT abnormalities) Grade
.gtoreq.3 AST or Hold fedratinib Grade .ltoreq.1 Fedratinib Hold
.ltoreq.14 ALT or total bilirubin Weekly monitoring of days: LFTs,
until Dose decrement by 1 resolution, dose level: 100 mg daily
After fedratinib decrease resumed, LFT Subsequent upward dose
monitoring every 2 titration not permitted weeks for the 3
Fedratinib Hold >14 subsequent cycles at a days (AE did not
return minimum to Grade .ltoreq.1): fedratinib permanently
discontinued Grade 4 in the absence of demonstrable cause:
permanently discontinue fedratinib Recurrence of LFT Discontinue --
-- abnormality (i.e. fedratinib .gtoreq.Grade 3 toxicity)
permanently after dose reduction Gastrointestinal Grade 2 nausea,
Hold fedratinib up to Toxicity resolves Consider resuming the
vomiting, diarrhea, or 14 days to Grade .ltoreq.1 dose at the same
level constipation that does after resolution of not respond to
adverse event adequate therapeutic or supportive measures within 48
hours Grade .gtoreq.3 or Hold fedratinib up to Toxicity resolves
Consider reducing one recurrence of Grade 2 14 days to Grade
.ltoreq.1 dose level after nausea vomiting, resolution of adverse
diarrhea, or event constipation that does not respond to adequate
therapeutic or supportive measures within 48 hours Other Adverse
Events Not Described Above Grade .gtoreq.3 or Hold fedratinib up to
Toxicity resolves Consider reducing one recurrence of Grade 2 14
days to Grade .ltoreq.1 dose level after that does not respond
resolution of adverse to adequate event therapeutic or supportive
measures within 48 hours Grade .gtoreq.3 non- Hold fedratinib up to
Toxicity resolved Dose decrement by 1 hematological 14 days to
Grade .ltoreq.1 dose level: 100 mg daily toxicity, non- decrease
gastrointestinal toxicity or Grade .gtoreq.2 peripheral
neuropathies
[0142] Dose Adjustment for Co-Administration with Strong and
Moderate CYP3A4 Inhibitors
[0143] Concomitant administration of fedratinib with strong or
moderate CYP3A4 inhibitors can increase fedratinib exposure.
Increased fedratinib exposure may increase the risk of
exposure-related AEs and need to be considered carefully.
[0144] For subjects with a co-administration of a strong CYP3A4
inhibitor a dose reduction of the starting dose of fedratinib from
400 mg to 200 mg is recommended. In case a strong CYP3A4 inhibitor
is required to be introduced during fedratinib treatment consider
dose reduction by 2 decrement dose level (e.g. 300 mg to 100 mg).
Strong CYP3A4 inhibitors include, but are not limited to,
boceprevir, cobicistat, conivaptan, danoprevir and ritonavir,
elvitegravir and ritonavir, grapefruit juice, indinavir and
ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir,
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir),
posaconazole, ritonavir, saquinavir and ritonavir, telaprevir,
tipranavir and ritonavir, troleandomycin, and voriconazole.
[0145] For subjects with a co-administration of a moderate CYP3A4
inhibitor a dose reduction from the starting dose of fedratinib
from 400 mg to 300 mg is recommended. In case a moderate CYP3A4
inhibitor is required to be introduced during fedratinib treatment
consider dose reduction by 1 decrement dose level (e.g. 300 mg to
200 mg). Moderate CYP3A4 inhibitors include, but are not limited
to, aprepitant, cimetidine, ciprofloxacin, clotrimazole,
crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole,
fluvoxamine, imatinib, tofisopam, and verapamil.
[0146] If the fedratinib dose needs to be reduced below 100 mg
daily based on any fedratinib related AEs due to a potentially
increased plasma concentration of fedratinib, consider a lower
average daily dose by administering, for example, 100 mg fedratinib
every other day that is equivalent to an average daily dose of 50
mg.
[0147] If AEs are still not resolved after reducing fedratinib
dose, consider interrupting dosing of either fedratinib or strong
CYP3A4 inhibitors based on overall benefit/risk for a patient.
[0148] In cases where co-administration with the CYP3A4 inhibitor
is discontinued, the fedratinib dose should be re-escalated
accordingly.
[0149] Dose adjustment for renal impairment. No dose adjustment is
recommended in subjects with mild and moderate renal impairment. In
subjects that develop severe renal impairment during the study the
fedratinib dose should be adjusted by one dose decrement level
(e.g. from 400 mg to 300 mg once a day [QD]). Subject on a planned
dose of 200 mg QD are allowed to reduce to 100 mg.
[0150] Management of Potential Wernicke's Encephalopathy (WE)
[0151] A potential case of WE is a medical emergency. Screening for
WE and management of potential cases of WE during treatment with
fedratinib will be done according the following steps:
[0152] Clinical and Cognitive Assessment. Interval history:
including a review of the subject's history for confusion, memory
problems, vision problems (e.g. double vision) as well as poor
nutrition, signs and symptoms of malabsorption, and alcohol use
[0153] Physical examination: including assessment for abnormal eye
movements, cerebellar abnormalities and body weight (weight loss
compared to previous examination or patient history) during
screening and Day 1 of every treatment cycle, at the End of
Treatment (EOT), and the 30-Day Follow-up visit [0154] Mini-Mental
State Examination (MMSE): to objectively assess for signs/symptoms
of encephalopathy during screening, on Day 1 of Cycles 2 and 3 and
every third cycle thereafter, at EOT, and more frequently as
clinically indicated
[0155] Management of Potential WE. In case of signs or symptoms
that may indicate WE: [0156] Hold fedratinib until WE is ruled out
[0157] Obtain sample for thiamine level [0158] Empirically start
thiamine supplementation [0159] Report the event as an AESI to the
Sponsor [0160] Obtain a neurological consult [0161] Perform a brain
MRI [0162] If WE is confirmed discontinue fedratinib
permanently
[0163] Thiamine Monitoring and Correction. Thiamine levels (for
whole blood) will be monitored and thiamine supplementation will be
administered to all subjects with thiamine levels below the normal
range. [0164] Thiamine levels are assessed at screening and need to
be corrected and retested before starting fedratinib treatment
[0165] While on treatment with fedratinib, thiamine levels are
assessed at start of Cycle 2, 3 and every third cycle thereafter or
as clinically indicated: [0166] If a subject is on thiamine
supplementation, thiamine levels should be assessed in a fasting
state for thiamine supplementation and thiamine given after the
blood draw [0167] If a thiamine level result is below normal, the
site will contact the subject as soon as possible to start thiamine
supplementation [0168] For thiamine levels below the normal range
but .gtoreq.30 nM/L without signs or symptoms of WE: [0169]
Supplementation with 100 mg oral thiamine must be started [0170] If
the results were obtained by a local laboratory, report the event
as an Adverse Event of Special Interest (AESI) to the Sponsor
[0171] For thiamine level <30 nM/L with or without signs or
symptoms of WE: [0172] Immediate treatment with thiamine
(preferably intravenous (IV)) at therapeutic dosages (e.g., 500 mg
infused over 30 minutes 3 times daily for 2 to 3 days) or
alternatively intramuscular (IM) in equivalent doses according to
local standard of care [0173] Report the event as an Adverse Event
of Special Interest (AESI) to the Sponsor [0174] This will be
followed by 250 mg to 500 mg IV thiamine infused once a day for 3
to 5 days or alternatively IM in equivalent doses according to
local standard of care [0175] And then continue at an oral daily
dose of 100 mg thiamine for at least 90 days [0176] Fedratinib must
be held until thiamine levels are restored to normal range. [0177]
Thiamine supplementation should be administered as a thiamine only
formulation. [0178] If thiamine levels are low, ensure that
magnesium levels are normal or corrected if low [0179] An Adverse
event of special interest (AESI) is one of scientific and medical
interest specific to understanding of the Investigational Product
and may require close monitoring and rapid communication by the
Investigator to the sponsor.
[0180] The following are considered to be Adverse Events of Special
Interest (AESI): [0181] Wernicke's encephalopathy (WE) or suspected
cases of WE associated with thiamine levels below normal range.
[0182] Thiamine levels below normal range with or without signs or
symptoms of WE [0183] New malignancy after start of study treatment
[0184] Progression of myelofibrosis to acute myeloid leukemia (AML)
[0185] Cardiac failure or cardiomegaly [0186] Grade 3 and 4
hyperlipasemia or Grade 3 and 4 hyperamylasemia according to CTCAE
criteria, v 5.0 or events of pancreatitis [0187] Grade 3 or 4
alanine transaminase (ALT), aspartate transaminase (AST), or total
bilirubin elevation or events of hepatotoxicity
[0188] Management of Nausea and Vomiting. Management of nausea and
vomiting during treatment with fedratinib will be done according
the following steps: [0189] Subjects will be provided management
instructions (including when to contact the study site) before the
start of treatment [0190] In order to mitigate for nausea and
vomiting events, it is recommended to take fedratinib with food
during an evening meal. [0191] It is highly recommended to use
anti-nausea/vomiting treatment prophylactically according to local
practice for the first 8 weeks of treatment (e.g., ondansetron). If
dimenhydrinate or other muscarinic receptor antagonists are used
for nausea and vomiting, administer these agents in the evening to
minimize drowsiness and other potential neurological AEs [0192]
Hold/reduce the dose of fedratinib according to Table 1 [0193]
Hospitalization may be indicated for Grade 3 or higher nausea or
vomiting or events that persist [0194] For medications that are
administered for prophylactic use of nausea and vomiting, if no
clinically significant nausea and vomiting occurs during the first
8 weeks of fedratinib treatment, consider weaning the subject off
these medications
[0195] Management of Diarrhea. Management of diarrhea during
treatment with fedratinib will be done according the following
steps: [0196] Subjects should have loperamide available at home and
should be provided with diarrhea management instructions (including
when to contact the study site) before the start of treatment
[0197] Loperamide should not be given as prevention in case the
subject does not experience diarrhea [0198] Treat with loperamide
as per local practice at the onset of diarrhea. Consider starting
loperamide at a 4 mg loading dose and then 2 mg after each
diarrheal bowel movement without exceeding 16 mg/24 hours [0199]
Dietary modifications including adequate hydration, avoidance of
lactose containing foods and alcohol, small meals with rice,
bananas, bread, etc. [0200] Hold/reduce the dose of fedratinib
according to Table 1 [0201] Hospitalization may be indicated for
Grade 3 or higher persisting diarrhea. [0202] Management of nausea,
vomiting and diarrhea will be assessed during the subject's visit
on Day 1 of every following 28-day cycle, at Day 15 of the first
three cycles and by a mandatory telephone contact at Day 8 of the
first cycle.
Overview of Key Efficacy Assessments
[0203] Unless otherwise specified, analysis of spleen volume
response will be performed on the efficacy evaluable population,
myelofibrosis symptom response analyses will be performed on the
MFSAF population and spleen size response analyses will be
performed on the safety population.
[0204] Spleen Volume Response Rate (RR) by MRI/CT. Response rate of
reduction in spleen volume is defined as proportion of subjects who
have a .gtoreq.35% reduction in spleen volume at the end of Cycle 6
as compared to baseline. The response rate and 95% confidence
interval will be provided. In addition, a descriptive summary of
spleen volumes measurements and percentage change from baseline
will be provided. Subjects with a missing MRI/CT spleen volume at
the end of Cycle 6 including those who meet the criteria for
progression of splenomegaly before the end of Cycle 6 will be
considered non-responders.
[0205] A sensitivity analysis will be conducted for response rate
of subjects who have a .gtoreq.25% reduction in spleen volume at
the end of Cycle 6 as compared to baseline.
[0206] Spleen Response Rate by Palpation (RRP). Spleen response
rate by palpation is the proportion of subjects with a spleen
response according to the IWG-MRT 2013 at the end of Cycle 6 as
compared to baseline. This will be calculated for subjects that
have an enlarged spleen (.gtoreq.5 cm below LCM) at baseline.
Subjects with a missing spleen size assessment at the end of Cycle
6 including those who meet the criteria for progression of
splenomegaly before the end of Cycle 6 will be considered not to be
responders. The response rate and 95% confidence interval will be
provided.
[0207] Symptom Response Rate (SRR). Symptom response rate (SRR) is
defined as the proportion of subjects with .gtoreq.50% reduction
from baseline to the end of Cycle 6 in total symptom score (TSS)
measured by MFSAF version 4.0. The SRR and 95% confidence interval
will be provided. The TSS will be defined as the sum of each of the
7 symptom scores (Gwaltney C, Paty J, Kwitkowski V E, Mesa R A,
Dueck A C, Papadopoulos E J, et al. Development of a harmonized
patient-reported outcome questionnaire to assess myelofibrosis
symptoms in clinical trials. Leuk Res. 2017 August; 59:26-31). To
allow indirect comparison with previous MF studies, a modified TSS
(Mesa R A, Gotlib J, Gupta V, Catalano J V, Deininger M W, Shields
A L, et al. Effect of ruxolitinib therapy on myelofibrosis-related
symptoms and other patient-reported outcomes in COMFORT-I: a
randomized, double-blind, placebo-controlled trial. J Clin Oncol.
2013 Apr. 1; 31(10):1285-92) will also be derived from the 6
symptoms considered (night sweats, pruritus, abdominal discomfort,
early satiety, pain under ribs on left side, bone or muscle pain)
and analysis of SRR will be also performed.
[0208] At each timepoint, the TSS (based on 7 symptoms) and the
modified TSS will be calculated. Descriptive summary statistics
(size, mean, standard deviation, median, range) will be provided
for baseline scores, postbaseline scores and change from baseline
for TSS, modified TSS and symptom scores.
[0209] Subjects without a baseline TSS >0 will be considered
non-evaluable (due to no place for symptom reduction) for the SRR
analysis. Subjects with a missing TSS at the end of Cycle 6 or who
had disease progression before the end of the Cycle 6 will be
considered non-responders.
[0210] Duration of Spleen Volume Response by MRI/CT (DR). Duration
of spleen volume response (DR) by MRI/CT is defined as time from
the first documented spleen response (ie, .gtoreq.35% reduction in
spleen volume) to the first documented spleen volume reduction
<35%. In the absence an event (ie subsequent spleen volume
reduction <35% before the analysis is performed), the DR will be
censored at the date of the last valid assessment performed before
the analysis performed date.
[0211] Duration of spleen volume response by MRI/CT scan will be
analyzed using Kaplan-Meier method. K-M estimates of the 25th,
50th, and 75th percentiles and the 95% confidence interval of
median will be provided. K-M curves will be plotted.
[0212] Duration of Spleen Response by Palpation (DRP). Duration of
spleen response by palpation (DRP) is defined as time from the
first documented palpable spleen response, according to the IWG-MRT
2013 to the time of the first documented loss of response according
to the IWG-MRT 2013. Duration of spleen response by palpation
according to the IWG-MRT 2013 criteria will be calculated for
subjects that have an enlarged spleen at baseline (.gtoreq.5 cm
below LCM), and that have a spleen response by palpation. In the
absence of an event (ie no loss of spleen response by palpation)
before the analysis is performed, the DRP will be censored at the
date of the last valid assessment performed before the analysis
performed date.
[0213] Duration of Symptoms Response (DSR). Duration of symptoms
response is defined as time from the first documented response in
TSS (ie, reduction in TSS .gtoreq.50%) measured by MFSAF version
4.0 to the first documented TSS reduction <50%. In the absence
of TSS reduction <50% before the analysis performed, the DSR
will be censored at the date of the last valid assessment performed
before the analysis performed date. DRS will be analyzed using K-M
method. The K-M estimates of the 25th, 50th, and 75th percentiles
and the 95% confidence intervals of median will be provided, and
K-M curves will be plotted.
TABLE-US-00002 TABLE 2 Study Endpoints Endpoint Name Description
Timeframe Primary Spleen volume Proportion of subjects who have a
From Screening to the response rate .gtoreq.35% reduction in spleen
volume at end of Cycle 6 the end of Cycle 6 Secondary Safety
profile of Incidence and severity of all Grade From ICF signature
up fedratinib adverse events (AEs) per NCI CTC until 30 days post
last Incidence and severity of Grade 34 dose AEs as per the NCI
CTC, including For fedratinib related laboratory parameters AEs,
anytime until the last study visit Spleen response rate Proportion
of subjects who have a From C1D1 to the end by palpation
.gtoreq.50% reduction in spleen size by of cycle 6 palpation
Symptom response Proportion of subjects with a .gtoreq. 50% From
C1D1 to the end rate reduction in total symptom scores of cycle 6
measured by MFSAF Durability of spleen Duration of .gtoreq.35%
reduction in From screening to the response spleen volume End of
Treatment visit Durability of spleen Duration of .gtoreq.50%
reduction in From C1D1 until the response by palpation spleen size
by palpation for subjects 30-day follow-up after with a palpable
spleen at least 5 cm last dose visit below the left costal margin
(LCM) at C1D1 Durability of Duration of .gtoreq.50% reduction in
total From C1D1 until the symptoms response symptom scores measured
by 30-day follow-up after MFSAF last dose visit Assessment of risk
Incidence of patients with a CTCAE From ICF signature to mitigation
strategy grade 3 of nausea, diarrhea, or the 30-day follow-up for
gastrointestinal vomiting, or occurrence of WE after last dose
visit adverse events and (confirmed by brain MRI or potential
Wernicke's autopsy). encephalopathy (WE) Assessment of thiamine
levels at screening, on Day 1 of the first 3 cycles and every third
cycle thereafter, and at the End of Treatment visit HRQoL measured
by Mean changes in the HRQoL From C1D1 to Day 1 EORTC QOL-C30
function and symptom domain of each cycle, at the domains scores
over the study compared with End of Treatment visit C1D1 up to the
30-day follow-up after last dose visit PRO measured by Mean changes
in the health utility From C1D1 to Day 1 EQ-5D-5L scores over the
study compared with of each cycle up to the enrollment measured by
EQ-5D-5L 30-day follow-up after last dose visit Exploratory Overall
Survival Time from C1D1 to death due to any From enrollment to 12
reason months after the End of Treatment visit Treatment-related
Assessment of the five selected From C1D1 to Day 1 symptoms from
the treatment-related symptoms from the of each cycle, at the
subject's perspecitve subject's perspective (diarrhea, End of
Treatment visit nausea, vomiting, dizziness, up to the 30-Day
headache) using the PRO-CTCAE follow-up after last dose visit
Prognostic markers Genetic alterations, including From C1D1 to End
of cytogenetics and gene mutations in Treatment visit peripheral
blood Mechanism of Action Circulating proteins, including From C1D1
to End of cytokines, immune and Treatment visit hematopoietic
markers AEs = adverse events; C1D1 = Cycle 1 Day 1; CTC = Common
Terminology Criteria for Adverse Events; ICF = informed consent
form; MFSAF = Myelofibrosis Symptom Assessment Form; MRI = magnetic
resonance imaging; NCI = National Cancer Institute; PRO-CTCAE =
Patient Reported Outcome Version of Common Terminology Criteria of
Adverse Events; SVR = spleen volume reduction.
[0214] Survival Follow-up Phase. All subjects discontinued from
protocol-prescribed therapy for any reason will be followed for
survival, subsequent therapies, new malignancy and progression of
myelofibrosis to acute myeloid leukemia (AML) every 3 months until
death or up to 12 months after end of treatment (EOT), lost to
follow-up, withdrawal of consent for further data collection, or
study closure.
* * * * *