WOLTORIO NEL MONDOWO DOMU .
`US 20170281619A1
`( 19 ) United States
`( 12 ) Patent Application Publication ( 10 ) Pub . No . : US 2017 / 0281619 A1
`Sampath et al .
`Oct . 5 , 2017
`( 43 ) Pub . Date :
`
`( 54 ) COMBINATION THERAPY OF A TYPE II
`ANTI - CD20 ANTIBODY WITH A SELECTIVE
`BCL - 2 INHIBITOR
`( 71 ) Applicants : GENENTECH , INC . , South San
`Francisco , CA ( US ) ; F .
`HOFFMANN - LA ROCHE AG , Basel
`( CH )
`( 72 ) Inventors : Deepak Sampath , South San Francisco ,
`CA ( US ) ; Christian Klein , Iffeldorf
`( DE ) ; Wayne John Fairbrother , South
`San Francisco , CA ( US )
`( 21 ) Appl . No . : 15 / 365 , 595
`( 22 ) Filed :
`Nov . 30 , 2016
`Related U . S . Application Data
`( 63 ) Continuation of application No . 14 / 020 , 761 , filed on
`Sep . 6 , 2013 , now Pat . No . 9 , 539 , 251 .
`
`( 60 ) Provisional application No . 61 / 698 , 379 , filed on Sep .
`7 , 2012 .
`
`Publication Classification
`
`Int . Cl .
`A61K 31 / 496
`( 2006 . 01 )
`U . S . CI .
`CPC . . . . . . . . A61K 31 / 496 ( 2013 . 01 ) ; A61K 2300 / 00
`( 2013 . 01 )
`
`ABSTRACT
`
`( 51 )
`( 52 )
`
`( 57 )
`
`The present invention is directed to a combination therapy
`involving a type II anti - CD20 antibody and a selective
`BCL - 2 inhibitor for the treatment of a patient suffering from
`cancer , particularly , a CD20 - expressing cancer .
`
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`FIG 3 / 5
`Schedule B Dosing Schema . Obinutuzumab Administered
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`DRL EXHIBIT 1013 PAGE 4
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`DRL EXHIBIT 1013 PAGE 5
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`FIG 5 / 5
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`DRL EXHIBIT 1013 PAGE 6
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`US 2017 / 0281619 A1
`
`Oct . 5 , 2017
`
`COMBINATION THERAPY OF A TYPE II
`ANTI - CD20 ANTIBODY WITH A SELECTIVE
`BCL - 2 INHIBITOR
`This application claims priority to United States
`[ 0001 ]
`Provisional No . 61 / 698 , 379 , filed Sep . 7 , 2012 , the content
`of which is incorporated herein by reference in its entirety .
`
`TECHNICAL FIELD
`[ 0002 ] The present invention is directed to a combination
`therapy involving a type II anti - CD20 antibody and a
`selective Bcl - 2 inhibitor for the treatment of a patient
`suffering from cancer , particularly a CD20 - expressing can
`cer .
`
`BACKGROUND
`[ 0003 ] The CD20 molecule ( also called human B - lympho
`cyte - restricted differentiation antigen or Bp35 ) is a hydro
`phobic transmembrane protein with a molecular weight of
`approximately 35 kD located on pre - B and mature B lym
`phocytes ( Valentine , M . A . , et al . , J . Biol . Chem . 264 ( 19 )
`( 1989 ) 11282 - 11287 ; and Einfield , D . A . , et al . EMBO J .
`7 ( 3 ) ( 1988 ) 711 - 717 ) . CD20 is found on the surface of
`greater than 90 % of B
`cells from peripheral blood or
`lymphoid organs and is expressed during early pre - B cell
`development and remains until plasma cell differentiation .
`CD20 is present on both normal B cells as well as malignant
`B cells . In particular , CD20 is expressed on greater than 90 %
`of B cell non - Hodgkin ' s lymphomas ( NHL ) ( Anderson , K .
`C . , et al . , Blood 63 ( 6 ) ( 1984 ) 1424 - 1433 ) but is not found on
`hematopoietic stem cells , pro - B cells , normal plasma cells ,
`or other normal tissues ( Tedder , T . F . , et al . , J , Immunol .
`135 ( 2 ) ( 1985 ) 973 - 979 ) .
`[ 0004 ] The 85 amino acid carboxyl - terminal region of the
`CD20 protein is located within the cytoplasm . The length of
`this region contrasts with that of other B cell - specific surface
`structures such as IgM , IgD , and IgG heavy chains or
`histocompatibility antigens class II a orß chains , which have
`relatively short intracytoplasmic regions of 3 , 3 , 28 , 15 , and
`16 amino acids , respectively ( Komaromy , M . , et al . , NAR II
`( 1983 ) 6775 - 6785 ) . Of the last 61 carboxyl - terminal amino
`acids , 21 are acidic residues , whereas only 2 are basic ,
`indicating that this region has a strong net negative charge .
`The GenBank Accession No . is NP - 690605 . It is thought
`that CD20 might be involved in regulating an early step ( s )
`in the activation and differentiation process of B
`cells
`( Tedder , T . F . , et al . , Eur . J . Immunol . 16 ( 1986 ) 881 - 887 )
`and could function as a calcium ion channel ( Tedder , T . F . ,
`et al . , J . Cell . Biochem . 14D ( 1990 ) 195 ) . There exist two
`different types of anti - CD20 antibodies which differ signifi
`cantly in their mode of CD20 binding and biological activi
`ties ( Cragg , M . S . , et al . , Blood 103 ( 2004 ) 2738 - 2743 ; and
`Cragg , M . S . , et al . , Blood 101 ( 2003 ) 1045 - 1052 ) . Type I
`antibodies , as e . g . rituximab , are potent in complement
`mediated cytotoxicity , whereas type II antibodies , as e . g .
`Tositumomab ( B1 ) , 11B8 , AT80 or humanized B - Lyl anti
`bodies , effectively initiate target cell death via caspase
`independent apoptosis with concomitant phosphatidylserine
`exposure .
`[ 0005 ] The shared common features of type I and type II
`anti - CD20 antibodies are summarized in Table 1 below .
`
`TABLE 1
`Properties of type I and type II anti - CD20 antibodies
`type II anti - CD20 antibodies
`type II CD20 epitope
`Do not localize CD20 to lipid rafts
`Decreased CDC ( if IgG1 isotype )
`ADCC activity ( if IgG1 isotype )
`Reduced binding capacity
`Stronger homotypic aggregation
`Strong cell death induction without
`cross - linking
`
`type I anti - CD20 antibodies
`type 1 CD20 epitope
`Localize CD20 to lipid rafts
`Increased CDC ( if IgG1 isotype )
`ADCC activity ( if IgG1 isotype )
`Full binding capacity
`Homotypic aggregation
`Apoptosis induction upon cross -
`linking
`
`[ 0006 ] The Bcl - 2 family of proteins regulates pro
`grammed cell death triggered by developmental cues and in
`response to multiple Stress signals ( Cory . S . , and Adams , J .
`M . , Nature Reviews Cancer 2
`( 2002 ) 647 - 656 ; Adams ,
`Genes und Development 17 ( 2003 ) 2481 - 2495 ; Danial , N .
`N . , and Korsmeyer , S . J . , Cell 116 ( 2004 ) 205 - 219 ) . Whereas
`cell survival is promoted by Bcl - 2 itself and several close
`relatives ( Bcl - xL , Bcl - W , Mcl - 1 and Al ) , which bear three
`or four conserved Bcl - 2 homology ( BH ) regions , apoptosis
`is driven by two other sub - families . The initial signal for cell
`death is conveyed by the diverse group of BH3 - only pro
`teins , including Bad , Bid , Bim , Puma and Noxa , which have
`in common only the small BH3 interaction domain ( Huang
`and Strasser , Cell 103 ( 2000 ) 839 - 842 ) . However , Bax or
`Bak , multi - domain proteins containing BH1 - BH3 , are
`required for commitment to cell death ( Cheng , W . X . , et al . ,
`Genes and Development 15 148 ( 2001 ) 1 - 1486 ) . When
`activated , they can permeabilize the outer membrane of
`mitochondria and release pro - apoptogenic factors ( e . g .
`cytochrome C ) needed to activate the caspases that dis
`mantle the cell ( Wang , K . , Genes and Development 15
`( 2001 ) 2922 - 2933 ; ( Adams , 2003 supra ) ; Green , D . R . , and
`Kroemer , G . , Science 305 ( 2004 ) 626 - 629 ) .
`[ 0007 ] Interactions between members of these three fac
`tions of the Bcl - 2 family dictate whether a cell lives or dies .
`When BH3 - only proteins have been activated , for example ,
`in response to DNA damage , they can bind via their BH3
`domain to a groove on their pro - survival relatives ( Sattler , et
`al . , Science 275 ( 1997 ) 983 - 986 ) . How the BH3 - only and
`Bcl - 2 - like proteins control the activation of Bax and Bak ,
`however , remains poorly understood ( Adams , 2003 supra ) .
`Most attention has focused on Bax . This soluble monomeric
`protein ( Hsu , Y . T . , et al . , Journal of Biological Chemistry
`272 ( 1997 ) 13289 - 1 3834 ; Wolter , K . G . , et al . , Journal of
`Cell Biology 139 ( 1997 ) 1281 - 92 ) normally has its mem
`brane targeting domain inserted into its groove , probably
`accounting for its cytosolic localization ( Nechushtan , A . , et
`al . , EMBO Journal 18 ( 1999 ) 2330 - 2341 ; Suzuki , et al . , Cell
`103 ( 2000 ) 645 - 654 ; Schinzel , A . , et al . , J Cell Biol 164
`( 2004 ) 1021 - 1032 ) . Several unrelated peptides / proteins
`have been proposed to modulate Bax activity , reviewed in
`Lucken - Ardjomande , S . , and Martinou , J . C . , J Cell Sci 118
`( 2005 ) 473 - 483 , but their physiological relevance remains to
`be established . Alternatively , Bax may be activated via
`direct engagement by certain BH3 - only proteins ( Lucken
`Ardjomande , S . , and Martinou , J . C . , 2005 supra ) , the best
`documented being a truncated form of Bid , tBid ( Wei , M . C . ,
`et al . , Genes and Development 14 ( 2000 ) 2060 - 2071 ;
`Kuwana , T . , et al . , Cell 111 ( 2002 ) 331 - 342 ; Roucou , X . , et
`al . , Biochemical Journal 368 ( 2002 ) 915 - 921 ; Cartron , P . F . ,
`et al . , Mol Cell 16 ( 2004 ) 807 - 818 ) . As discussed elsewhere
`
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`
`( Adams 2003 supra ) , the oldest model , in which Bcl - 2
`directly engages Bax ( Oltvai , Z . N . , et al . , Cell 74 ( 1993 )
`609 - 619 ) , has become problematic because Bcl - 2 is mem
`brane bound while Bax is cytosolic , and their interaction
`seems highly dependent on the detergents used for cell lysis
`( Hsu , Y . T . , and Youle , 1997 supra ) . Nevertheless , it is well
`established that the BH3 region of Bax can mediate asso
`ciation with Bcl - 2 ( Zha , H . , and Reed , J . , Journal of Bio
`logical Chemistry 272 ( 1997 ) 31482 - 88 ; Wang , K . , et al . ,
`Molecular und Cellular Biology 18 ( 1998 ) 6083 - 6089 ) and
`that Bcl - 2 prevents the oligomerization of Bax , even though
`no heterodimers can be detected ( Mikhailov , V . , et al . ,
`Journal of Biological Chemistry 276 ( 2001 ) 18361 - 18374 ) .
`Thus , whether the pro - survival proteins restrain Bax activa
`tion directly or indirectly remains uncertain .
`10008 ] Although Bax and Bak seem in most circumstances
`to be functionally equivalent ( Lindsten , T . , et al . , Molecular
`Cell 6 ( 2000 ) 1389 - 1399 ; Wei , M . C . , et al . , 2001 supra ) ,
`substantial differences in their regulation would be expected
`from their distinct localization in healthy cells . Unlike Bax ,
`which is largely cytosolic , Bak resides in complexes on the
`outer membrane of mitochondria and on the endoplasmic
`reticulum of healthy cells ( Wei , M . C . , et al . , 2000 supra ;
`Zong , W . X . , et al . , Journal of Cell Biology 162 ( 2003 )
`59 - 69 ) . Nevertheless , on receipt of cytotoxic signals , both
`Bax and Bak change conformation , and Bax translocates to
`the organellar membranes , where both Bax and Bak then
`form homo - oligomers that can associate , leading to mem
`brane permeabilization ( Hsu , Y . T . , et al . , PNAS 94 ( 1997 )
`3668 - 3672 ; Wolter , K . G . , et al . , 1997 supra ; Antonsson , B . ,
`et al . , Journal of Biological Chemistry 276 ( 2001 ) 11615
`11623 ; Nechushtan , A . , et al . , Journal of Cell Biology 153
`( 2001 ) 1265 - 1276 ; Wei , M . C . , et al . , 2001 supra ; Mikhailov ,
`V . , et al . , Journal of Biological Chemistry 278 ( 2003 )
`5367 - 5376 ) .
`[ 0009 ]
`There exist various Bcl - 2 inhibitors , which all have
`the same property of inhibiting prosurvival members of the
`Bcl - 2 family of proteins and are therefore promising candi
`dates for the treatment of cancer . Such Bcl - 2 inhibitors are
`e . g . Oblimersen , SPC - 2996 , RTA - 402 , Gossypol , AT - 101 ,
`Obatoclax mesylate , A - 371191 , A - 385358 , A - 438744 , ABT
`737 , ABT - 263 , AT - 101 , BL - 11 , BL - 193 , GX - 15 - 003 ,
`2 - Methoxyantimycin A3 , HA - 14 - 1 , KF - 67544 , Purpurogal
`lin , TP - TW - 37 , YC - 137 and Z - 24 , and are described e . g . in
`Zhai , D . , et al . , Cell Death and Differentiation 13 ( 2006 )
`1419 - 1421 .
`[ 0010 ] Smith , M . R . , et al , Molecular Cancer Therapeutics
`3 ( 12 ) ( 2004 ) 1693 - 1699 and Ramanarayanan , J . et al . ,
`British Journal of Haematology 127 ( 5 ) ( 2004 ) 519 - 530 ,
`refer to a combination of a type I anti - CD20 antibody
`( rituximab )
`with
`antisense Bcl - 2
`oligonucleotides
`( Oblimersen ) .
`SUMMARY OF THE INVENTION
`[ 0011 ] Provided herein are methods for the treatment of a
`patient suffering from cancer , comprising co - administering ,
`to a patient in need of such treatment , a type II anti - CD20
`antibody and a selective Bcl - 2 inhibitor . The co - administra
`tion may be simultaneous or sequential in either order .
`[ 0012 ] An example of the type II anti - CD20 antibody for
`use in the present invention is a GA101 antibody .
`[ 0013 ]
`In an embodiment , the type II anti - CD20 antibody
`has increased antibody dependent cellular cytotoxicity
`( ADCC ) .
`
`In an embodiment , at least 40 % of the oligosac
`[ 0014 ]
`charides of the Fc region of said type II anti - CD20 antibody
`are non - fucosylated .
`0015 ]
`In an embodiment , the selective Bcl - 2 inhibitor is
`GDC - 0199 ( also known as ABT - 199 ) , or a pharmaceutically
`acceptable salt thereof .
`[ 0016 ]
`In an embodiment , the cancer is a non - solid tumor .
`10017 ]
`In certain embodiments , methods are provided for
`the treatment of a cancer in a human in need thereof
`comprising administering to said human a GA101 antibody
`and / or GDC - 0199 in multiple dosing cycles . In an embodi
`ment , each dosing cycle of the multiple dosing cycle is for
`at least 1 week . In an embodiment , each dosing cycle of the
`multiple dosing cycle is for at 2 , for at least 3 , for at least 4 ,
`for at least 5 , or for at least 6 weeks .
`[ 0018 ]
`In an embodiment wherein the GA101 antibody
`and GDC - 0199 are administered to the human in multiple
`dosing cycles , GA101 antibody can , for example , be admin
`istered once per dosing cycle for one or more dosing cycles
`of the multiple dosing cycles . The amount of GA101 admin
`istered per dose can , for example , be between about 300 mg
`to about 3000 mg , or between about 500 mg to about 3000
`mg , or about 500 mg to about 1200 mg .
`[ 0019 ]
`In an embodiment wherein the GA101 antibody
`and GDC - 0199 are administered to the human in multiple
`dosing cycles , GDC - 0199 can , for example , be administered
`each day in a dosing cycle for one or more dosing cycles of
`the multiple dosing cycles . In an embodiment , GDC - 0199 is
`administered in fewer than all of the days of the initial
`dosing cycle , and is administered each day of the dosing
`cycles of the multiple dosing cycles that follow the initial
`dosing cycle . The amount of GDC - 0199 administered per
`day can be between about 10 mg to about 1 , 000 mg , about
`20 mg to about 800 mg , about 20 mg to about 500 mg , or
`between about 50 mg to about 300 mg .
`[ 0020 ]
`In an embodiment , both the GA101 antibody and
`GDC - 0199 are administered to the patient in at least 2 , 3 , 4 ,
`5 , 6 , 7 , 8 , or more than 8 , dosing cycles of the multiple
`dosing cycles .
`[ 0021 ]
`In certain embodiments of the methods provided
`for the treatment of a cancer in a human in need thereof
`comprising administering to said human both a GA101
`antibody and GDC - 0199 in multiple dosing cycles , follow
`ing the last dosing cycle of multiple dosing cycles , GDC
`0199 alone can be administered to the human in the absence
`of the GA101 antibody , or the GA101 antibody alone can be
`administered to the patient in the absence of GDC - 0199 . For
`instance , when GDC - 0199 is administered alone to the
`human ( e . g . , following the last cycle of multiple dosing
`cycles wherein both GDC - 0199 and the GA101 antibody are
`administered to the human ) , GDC - 0199 can be administered
`to the human for at least 3 , 4 , 5 , 6 , 7 , 8 or 9 days , or for 10
`or more days , for 20 or more days , or for 30 or more days .
`[ 0022 ] .
`In yet another embodiment of the methods pro
`vided wherein a GA101 antibody and GDC - 0199 are admin
`istered to the patient in multiple dosing cycles , the multiple
`dosing cycles comprise an escalating dosing cycle in which
`GDC - 0199 is administered to the patient in escalating daily
`dose amounts during the escalating dosing cycle .
`DESCRIPTION OF THE FIGURES
`[ 0023 ] FIG . 1 . Antitumor activity of combined treatment
`of a type II anti - CD20 antibody ( GA101 antibody , in this
`case , obinutuzumab ) with a Bcl - 2 inhibitor ( ABT - 199 , a . k . a .
`
`DRL EXHIBIT 1013 PAGE 8
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`Oct . 5 , 2017
`
`GDC - 0199 ) . Arrows and line under the x - axis indicates the
`days of dosing of GA101 and GDC - 0199 , respectively .
`[ 0024 ]
`FIG . 2 . Exemplary dosing schedule for adminis
`tering GDC - 199 with obinutuzumab .
`[ 0025 ]
`FIG . 3 . Exemplary dosing schedule for adminis
`tering GDC - 199 with obinutuzumab .
`[ 0026 ]
`FIG . 4 . Antitumor activities of a type II anti - CD20
`antibody ( obinutuzumab , a . k . a . RO5072759 ) used alone or
`in combination with GDC - 0199 , and of a type I anti - CD20
`antibody ( rituximab ) used alone or in combination with
`GDC - 0199 on human Z138 mantle cell lymphoma cells .
`[ 0027 ] FIG . 5 . Results from xenograft model of aggressive
`lymphoma demonstrating that single agent treatment with
`GDC - 0199 following combination of GDC - 0199 with type
`II anti - CD20 antibody ( GA101 antibody , in this case , obi
`nutuzumab ) delays tumor regrowth .
`DETAILED DESCRIPTION OF THE
`INVENTION
`the method
`10028 ] The present invention relates to
`described above . The present invention also relates to a
`method for the treatment of a human in need thereof
`comprising administering to said human an effective amount
`of a GA101 antibody or 2 - ( 2H - pyrrolo [ 2 , 3 - b ] pyridin - 4
`yloxy ) - 4 - ( ( 2 - ( 4 - chlorophenyl ) - 4 , 4 - dimethyleyclohex - 1
`enyl ) methyl ) piperazin - 1 - yl ) - N - ( 3 - nitro - 4 - ( ( tetrahydro - 2H
`pyran - 4 - yl ) methylamino ) phenylsulfonyl ) benzamide or a
`pharmaceutically acceptable salt thereof for one or more
`dosing periods , followed by co - administering an effective
`amount of said GA101 antibody and 2 - ( 2H - pyrrolo [ 2 , 3 - b ]
`pyridin - 4 - yloxy ) - 4 - ( ( 2 - ( 4 - chlorophenyl ) - 4 , 4 - dimethyley
`clohex - 1 - enyl ) methyl ) piperazin - 1 - yl ) - N - ( 3 - nitro - 4 - ( ( tetra
`hydro - 2H - pyran - 4 - yl ) methylamino ) phenylsulfonyl )
`benzamide or a pharmaceutically acceptable salt thereof for
`one or more dosing periods .
`[ 0029
`The present invention also relates to a method for
`the treatment of a human in need thereof comprising admin
`istering to said human an effective amount of a GA101
`antibody or 2 - ( 2H - pyrrolo [ 2 , 3 - b ] pyridin - 4 - yloxy ) - 4 - ( ( 2 - ( 4
`chlorophenyl ) - 4 , 4 - dimethyleyclohex - l - enyl ) methyl ) piper
`azin - 1 - yl ) - N - ( 3 - nitro - 4 - ( ( tetrahydro - 2H - pyran - 4 - yl ) methyl
`amino ) phenylsulfonyl ) benzamide for 0 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ,
`9 , 10 , 11 , 12 , 13 , or 14 days , followed by co - administering
`an effective amount of said GA101antibody and 2 - ( 2H
`pyrrolo [ 2 , 3 - b ] pyridin - 4 - yloxy ) - 4 - ( 2 - ( 4 - chlorophenyl ) - 4 , 4
`dimethyleyclohex - 1 - enyl ) methyl ) piperazin - 1 - yl ) - N - ( 3 - ni
`tro - 4 - ( ( tetrahydro - 2H - pyran - 4 - yl ) methylamino )
`phenylsulfonyl ) benzamide or a pharmaceutically acceptable
`salt thereof for one or more dosing periods .
`[ 0030 ] The present invention also relates to a method for
`the treatment of a human in need thereof comprising admin
`istering an effective amount of said GA101 antibody for 1 ,
`2 , 3 , 4 , 5 , 6 , or 7 days , followed by co - administering an
`effective amount of said GA101 antibody antibody and
`2 - ( 2H - pyrrolo [ 2 , 3 - b ] pyridin - 4 - yloxy ) - 4 - ( ( 2 - ( 4 - chlorophe
`nyl ) - 4 , 4 - dimethyleyclohex - 1 - enyl ) methyl ) piperazin - 1 - yl )
`N - ( 3 - nitro - 4 - ( ( tetrahydro - 2H - pyran - 4 - yl ) methylamino ) phe
`nylsulfonyl ) benzamide or a pharmaceutically acceptable salt
`thereof for one or more dosing periods .
`[ 0031 ]
`The present invention also relates to a method for
`the treatment of a human in need thereof comprising admin
`istering an effective amount of 2 - ( 2H - pyrrolo [ 2 , 3 - b ] pyridin
`4 - yloxy ) - 4 - ( 2 - ( 4 - chlorophenyl ) - 4 , 4 - dimethyleyclohex - 1
`enyl ) methyl ) piperazin - 1 - yl ) - N - ( 3 - nitro - 4 - ( ( tetrahydro - 2H
`
`pyran - 4 - yl ) methylamino ) phenylsulfonyl ) benzamide or a
`pharmaceutically acceptable salt thereof for 1 , 2 , 3 , 4 , 5 , 6 ,
`or 7 days , followed by co - administering an effective amount
`of said GA101 antibody antibody and 2 - ( 2H - pyrrolo [ 2 , 3 - b ]
`pyridin - 4 - yloxy ) - 4 - ( ( 2 - ( 4 - chlorophenyl ) - 4 , 4 - dimethyley
`clohex - 1 - enyl ) methyl ) piperazin - 1 - yl ) - N - ( 3 - nitro - 4 - ( ( tetra
`hydro - 2H - pyran - 4 - yl ) methylamino ) phenylsulfonyl )
`benzamide or a pharmaceutically acceptable salt thereof for
`one or more dosing periods .
`[ 0032 ] The present invention also relates to a method for
`the treatment of a human in need thereof comprising admin
`istering an effective amount of said GA101antibody once
`every dosing period for 1 , 2 , 3 , 4 , 5 or 6 cycles , followed by
`co - administering
`an
`effective
`amount of
`said
`GA101antibody antibody once every dosing period and
`2 - ( 2H - pyrrolo [ 2 , 3 - b ] pyridin - 4 - yloxy ) - 4 - ( ( 2 - ( 4 - chlorophe
`nyl ) - 4 , 4 - dimethyleyclohex - 1 - enyl ) methyl ) piperazin - 1 - yl )
`N - ( 3 - nitro - 4 - ( ( tetrahydro - 2H - pyran - 4 - yl ) methylamino )
`phen or a pharmaceutically acceptable salt thereof one , two
`phen or a pharmaceutically acceptable sall thereof one , two
`or three times a day for one or more dosing periods .
`[ 0033 ] The present invention also relates to a method for
`the treatment of a human in need thereof comprising admin
`istering an effective amount of 2 - ( 2H - pyrrolo [ 2 , 3 - b ] pyridin
`4 - yloxy ) - 4 - ( ( 2 - ( 4 - chlorophenyl ) - 4 , 4 - dimethyleyclohex - 1
`enyl ) methyl ) piperazin - 1 - yl ) - N - ( 3 - nitro - 4 - ( ( tetrahydro - 2H
`pyran - 4 - yl ) methylamino ) phenylsulfonyl ) benzamide or a
`pharmaceutically acceptable salt thereof one , two or three
`times a day for 1 , 2 , 3 , 4 , 5 or 6 dosing periods , followed by
`co - administering
`an
`effective
`amount of said
`GA101 antibody once every dosing period and 2 - ( 2H - pyr
`rolo [ 2 , 3 - b ] pyridin - 4 - yloxy ) - 4 - ( ( 2 - ( 4 - chlorophenyl ) - 4 , 4 - di
`methyleyclohex - l - enyl ) methyl ) piperazin - 1 - yl ) - N - ( 3 - nitro
`4 - ( ( tetrahydro - 2H - pyran - 4 - yl ) methylamino ) phenylsulfonyl )
`benzamide or a pharmaceutically acceptable salt thereof
`one , two or three times a day for one or more dosing periods .
`[ 0034 ] The present invention also relates to any one of the
`above methods , wherein the effective amount of said
`GA101 antibody is 500 , 600 , 700 , 800 , 900 , 1000 , 1100 ,
`1200 , 1300 , 1400 , 1500 , 1600 , 1700 , 1800 , 1900 , 2000 ,
`2100 , 2200 , 2300 , 2400 , 2500 , 2600 , 2700 , 2800 , 2900 , or
`3000 mg and the effective amount of 2 - ( 2H - pyrrolo [ 2 , 3 - b ]
`pyridin - 4 - yloxy ) - 4 - ( ( 2 - ( 4 - chlorophenyl ) - 4 , 4 - dimethyley
`clohex - 1 - enyl ) methyl ) piperazin - 1 - yl ) - N - ( 3 - nitro - 4 - ( ( tetra
`hydro - 2H - pyran - 4 - yl ) methylamino ) phenylsulfonyl )
`benzamide or a pharmaceutically acceptable salt thereof is
`10 , 20 , 30 , 40 , 50 , 60 , 70 , 80 , 90 , 100 , 110 , 120 , 130 , 140 ,
`150 , 160 , 170 , 180 , 190 , 200 , 210 , 220 , 230 , 240 , 250 , 260 ,
`270 , 280 , 290 , 300 , 310 , 320 , 330 , 340 , 350 , 360 , 370 , 380 ,
`390 , 400 , 410 , 420 , 430 , 440 , 450 , 460 , 470 , 480 , 490 , 500 ,
`510 , 520 , 530 540 , 550 , 560 , 570 , 580 , 590 , 600 , 610 , 620 ,
`630 , 640 , 650 , 660 , 670 , 680 , 690 , 700 , 710 , 720 , 730 , 740 ,
`750 , 760 , 770 , 780 , 790 , 800 , 810 , 820 , 830 , 840 , 850 , 860 ,
`870 , 880 , 890 , 900 , 910 , 920 , 930 , 940 , 950 , 960 , 970 , 980 ,
`990 , or 1000 mg .
`100351 The present invention also relates to any one of the
`above methods , wherein the effective amount of said
`GA101antibody is 800 , 900 , 1000 , 1100 , 1200 , 1300 , 1400
`or 1500 mg , and the effective amount of 2 - ( 2H - pyrrolo [ 2 ,
`3 - b ] pyridin - 4 - yloxy ) - 4 - ( ( 2 - ( 4 - chlorophenyl ) - 4 , 4 - dimethyl
`eyclohex - 1 - enyl ) methyl ) piperazin - 1 - yl ) - N - ( 3 - nitro - 4 - ( ( tet
`rahydro - 2H - pyran - 4 - yl ) methylamino ) phenylsulfonyl )
`benzamide or a pharmaceutically acceptable salt thereof is
`
`DRL EXHIBIT 1013 PAGE 9
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`US 2017 / 0281619 A1
`
`Oct . 5 , 2017
`
`50 , 60 , 70 , 80 , 90 , 100 , 110 , 120 , 130 , 140 , 150 , 160 , 170 ,
`180 , 190 , 200 , 210 , 220 , 230 , 240 , 250 , 260 , 270 , 280 , 290
`or 300 mg .
`[ 0036 ) . The present invention also relates to any one of the
`above methods , wherein when said cancer is NHL , the
`effective amount of said GA101 antibody is 800 , 900 , 1000 ,
`1100 , 1200 , 1300 , 1400 or 1500 mg , and the effective
`amount of 2 - ( 2H - pyrrolo [ 2 , 3 - b ] pyridin - 4 - yloxy ) - 4 - ( ( 2 - ( 4
`chlorophenyl ) - 4 , 4 - dimethyleyclohex - 1 - enyl ) methyl ) piper
`azin - 1 - yl ) - N - ( 3 - nitro - 4 - ( ( tetrahydro - 2H - pyran - 4 - yl ) methyl
`aminophenylsulfonyl ) benzamide or a pharmaceutically
`acceptable salt thereof is 50 , 60 , 70 , 80 , 90 , 100 , 110 , 120 ,
`130 , 140 , 150 , 160 , 170 , 180 , 190 , 200 , 210 , 220 , 230 , 240 ,
`250 , 260 , 270 , 280 , 290 , 300 , 310 , 320 , 330 , 340 , 350 , 360 ,
`370 , 380 , 390 , 400 , 410 , 420 , 430 , 440 , 450 , 460 , 470 , 480 ,
`490 , 500 , 510 , 520 , 530 540 , 550 , 560 , 570 , 580 , 590 , 600 ,
`610 , 620 , 630 , 640 , 650 , 660 , 670 , 680 , 690 , 700 , 710 , 720 ,
`730 , 740 , 750 , 760 , 770 , 780 , 790 , and 800 mg .
`[ 00371 . The present invention also relates to any one of the
`above methods , wherein when said cancer is AML , the
`effective amount of said GA101 antibody is 800 , 900 , 1000 ,
`1100 , 1200 , 1300 , 1400 or 1500 mg , and the effective
`amount of 2 - ( 2H - pyrrolo [ 2 , 3 - b ] pyridin - 4 - yloxy ) - 4 - ( 2 - ( 4
`chlorophenyl ) - 4 , 4 - dimethyleyclohex - 1 - enyl ) methyl ) piper
`azin - 1 - yl ) - N - ( 3 - nitro - 4 - ( ( tetrahydro - 2H - pyran - 4 - yl ) methyl
`amino ) phenylsulfonyl ) benzamide or a pharmaceutically
`acceptable salt thereof is 50 , 60 , 70 , 80 , 90 , 100 , 110 , 120 ,
`130 , 140 , 150 , 160 , 170 , 180 , 190 , 200 , 210 , 220 , 230 , 240 ,
`250 , 260 , 270 , 280 , 290 , 300 , 310 , 320 , 330 , 340 , 350 , 360 ,
`370 , 380 , 390 , 400 , 410 , 420 , 430 , 440 , 450 , 460 , 470 , 480 ,
`490 , 500 , 510 , 520 , 530 540 , 550 , 560 , 570 , 580 , 590 , 600 ,
`610 , 620 , 630 , 640 , 650 , 660 , 670 , 680 , 690 , 700 , 710 , 720 ,
`730 , 740 , 750 , 760 , 770 , 780 , 790 , and 800 mg .
`[ 0038 ]
`The present invention also relates to any one of the
`above methods , wherein said GA10antibody and 2 - ( 2H
`pyrrolo [ 2 , 3 - b ] pyridin - 4 - yloxy ) - 4 - ( ( 2 - ( 4 - chlorophenyl ) - 4 , 4
`dimethyleyclohex - 1 - enyl ) methyl ) piperazin - 1 - yl ) - N - ( 3 - ni
`tro - 4 - ( ( tetrahydro - 2H - pyran - 4 - yl ) methylamino )
`phenylsulfonyl ) benzamide or a pharmaceutically acceptable
`salt thereof were co - administered sequentially during each
`dosing period , and each dosing period is 5 , 6 , 7 , 8 , 9 , 10 , 11 ,
`12 , 13 , or 14 days .
`[ 0039 ] The term “ antibody ” herein is used in the broadest
`sense and encompasses various antibody structures , includ
`ing but not limited to monoclonal antibodies , polyclonal
`antibodies , multispecific antibodies ( e . g . , bispecific antibod
`ies ) , and antibody fragments so long as they exhibit the
`desired antigen - binding activity .
`10040 ]
`The term “ monoclonal antibody ” as used herein
`refers to an antibody obtained from a population of substan
`tially homogeneous antibodies , i . e . , the individual antibod
`ies comprising the population are identical and / or bind the
`same epitope , except for possible variant antibodies