IL295626A - A triple pharmaceutical combination comprising dabrafenib, an erk inhibitor and a raf inhibitor - Google Patents

A triple pharmaceutical combination comprising dabrafenib, an erk inhibitor and a raf inhibitor

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Publication number
IL295626A
IL295626A IL295626A IL29562622A IL295626A IL 295626 A IL295626 A IL 295626A IL 295626 A IL295626 A IL 295626A IL 29562622 A IL29562622 A IL 29562622A IL 295626 A IL295626 A IL 295626A
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Israel
Prior art keywords
braf
dabrafenib
compound
seq
pharmaceutic
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IL295626A
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Hebrew (he)
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Novartis Ag
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Publication of IL295626A publication Critical patent/IL295626A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Description

WO 2021/171260 PCT/IB2021/051641 A TRIPLE PHARMACEUTICAL COMBINATION COMPRISING DABRAFENIB, AN ERK INHIBITOR AND A RAF INHIBITOR OR A PD-1 INHIBITOR.
FIELD OF THE INVENTION id="p-1" id="p-1" id="p-1" id="p-1" id="p-1"
[0001] The present invention relate to sa pharmaceutic combinatal ioncomprising: id="p-2" id="p-2" id="p-2" id="p-2" id="p-2"
[0002] (i). dabrafenib, or a pharmaceutica accllyepta saltble there of,an Erk inhibitor (ERKi) such as 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazi n-2-yl)-N- ((S)- l-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2 -fluor("Compoundobenz A"amide or "compound A"), or a pharmaceutica accllyepta saltble there of,and a RAF inhibit orsuch as N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-( trifluoromethyl)- isonicotinami ("Compoundde C") or a pharmaceutic accallyepta saltble there of;or id="p-3" id="p-3" id="p-3" id="p-3" id="p-3"
[0003] (ii). dabrafenib, or a pharmaceutica accllyepta salble theret of,an Erk inhibitor (ERKi) such as 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazi n-2-yl)-N- ((S)-l-(3-brorno-5-fluorophenyl)-2-(methylarnino)ethyl)-2- ("Compoundfluorobenz A" amide or "compound A"), or a pharmaceutica accllyepta saltble there of,and a PD-1 inhibit orsuch as Spartalizumab; and pharmaceut compoical sitions comprisin theg same comme; rci packagesal comprisin theg same; and methods of using such combinations and compositions in the treatment or prevention of conditions in which MAPK pathway inhibition is beneficial for , example, in the treatment of cance rs.The prese ntinvention als povideso such combinations for use in the treatments of such conditions or cancers, including colore ctalcance (CRC)r such as BRAF gain of functi oncolorect cancer.al BACKGROUND OF THE INVENTION id="p-4" id="p-4" id="p-4" id="p-4" id="p-4"
[0004] The MAPK pathway is a key signaling cascade that drives cell proliferation, differentiation, and surviva Dysregl. ulation of this pathway underlies many instances of tumorigenesi Abers. rant signaling or inappropr iateactivati ofon the MAPK pathway has been shown in multiple tumor types and can occur through severa distincl mect hanis ms,including activat mutating ions in RAS and BRAF. The MAPK pathway is frequently mutat edin human 1WO 2021/171260 PCT/IB2021/051641 cance withr KRAS and BRAF mutations being among the most frequent (approximately 30%).
RAS mutations, particularly gain of function mutations have, been detecte in d9-30% of all cancers, with KRAS mutations having the highest prevalence (86%). id="p-5" id="p-5" id="p-5" id="p-5" id="p-5"
[0005] The extracellular signal-regulat kinasesed (ERKs) are one clas ofs signaling kinases that are involv ined conveyi extrang cellular signal intos cells and subcellula r organelle ERK1s. and ERK2 are involv ined regulati ang wide range of activitie ands dysregulat ofion the ERK1/2 cascade is known to cause a variet ofy pathologies including neurodegener diseaativeses, development disealases diabet, esand cancer. The role of ERK1/2 in cance isr of special intere becausest activating mutations upstream of ERK1/2 in its signaling cascade are believed to be responsibl fore more than half of all cancers .
Moreover, excessive ERK1/2 activity was als ofound in cancer whers thee upstrea m compone ntswer enot mutated, suggesti thatng ERK1/2 signaling plays a role in carcinogene evensis in cancers without mutationa activations.l The ERK pathway has also been shown to control tumor cell migrat ionand invasion, and thus may be associated with metastasis. id="p-6" id="p-6" id="p-6" id="p-6" id="p-6"
[0006] The Programmed Death 1 (PD-1) protein is an inhibito memry ber of the extended CD28/CTLA-4 family of T cel regul lat orsTwo. ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD-L2 (B7-DC), that have been shown to downregulate T cel activatl uponion binding to PD-1. PD-L1 is abunda ntin a varie ofty human cancers PD-1. is known as an immunoinhibitor protey thatin negatively regulate TCRs signa ls.The interaction between PD-1 and PD-L1 can ac tas an immune checkpoint, which can lea to,d for example a ,decrease in tumor infiltrating lymphocytes, a decrease in T-cel recel ptor mediate prolid feration, and/or immun e evasion by cancerous cells Imm. une suppressi oncan be revers byed inhibiting the loca l interac tionof PD-1 with PD-L1 or PD-L2; the effe ctis additi vewhen the interac tionof PD-1 with PD-L2 is blocked as well. id="p-7" id="p-7" id="p-7" id="p-7" id="p-7"
[0007] Given the importance of immun echeckpoint pathways in regulat aning immune response the, need exist fors developing novel combination therapi thates activate the immune system. The prognosis for patien suffets ring from certa cancersin remains poor. Resistanc to e treatment occurs frequently and not all patients respond to availabl tree atme ntsFor exampl. e, the median survival for patients suffering from advanced colorecta cancel witr hBRAF mutation is les thans 12 months. It is thus importa tont develop new therapies for patients 2WO 2021/171260 PCT/IB2021/051641 suffering from cance tor achieve better clinica outcomes.l Treatment options which are bette r tolerated and/o provider durable anti-tumor response ares also desired.
SUMMARY OF THE INVENTION id="p-8" id="p-8" id="p-8" id="p-8" id="p-8"
[0008] The triple combinations of the prese ntinvention (i) dabrafenib an ;Erk- inhibit orsuch as Compound A, and a RAF-inhibit orsuch as compound C; or (ii) dabrafenib, an Erk-inhibito suchr as Compound A, and a PD-1 inhibit orsuch as Spartalizuma canb, be used as therapies for the treatmen of diset ase ors disorder resuls ting from the aberrant activity of the MAPK pathway including, but not limite to,d breas canct er, cholangiocarcinoma, salivar glandy cance colorr, ecta cancl er, melanoma, non-smal celll lung cancer, ovari an cance andr thyroid cancer. Triple combinations of dabrafenib, an Erk-inhibito suchr as Compound A, and a RAF-inhibit orsuch as compound C, or dabrafenib, an Erk-inhibit suchor as Compound A, and a PD-1 inhibit orsuch as Spartalizuma areb, particularly useful in the treatment of colore ctalcance (CRC),r including advanced or metastati colorc ecta cancl er, which is BRAF gain of functi onor BRAFV600E/D/K mutants. id="p-9" id="p-9" id="p-9" id="p-9" id="p-9"
[0009] The present invention provides a pharmaceut combinaical tion comprising: (a) N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2-fluoroph enyl)-2,6- difluorobenzenesulfonamide (dabrafen orib), a pharmaceutic accallyepta sablelt thereof, having the structure: (b) 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S) -l-(3- bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-f (Comluorobenzapound A), oramide pharmaceutic acceptaally sablelt there of,having the structure: 3WO 2021/171260 PCT/IB2021/051641 Q, OH ; and (c) N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)-isonicot (Compouninamide C),d or a pharmaceutic accallyepta salble t there of,having the structure: id="p-10" id="p-10" id="p-10" id="p-10" id="p-10"
[0010] The present invention provide a spharmaceutic combinaal tion comprising: (a) N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)-2,6- difluorobenzenesulfonamide (dabrafen orib), a pharmaceutica acceptally saltble thereof, having the structure: (b) 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S) -l-(3- bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-f (Comluorobenzapound A), oramide pharmaceutic acceptaally sablelt there of,having the structure: 4WO 2021/171260 PCT/IB2021/051641 OH ; and (c) a PD-1 inhibitor. id="p-11" id="p-11" id="p-11" id="p-11" id="p-11"
[0011] In a furthe asper ct of the invention, the PD-1 inhibit oris chose fromn PDR001 (spartalizumab; Novartis) Nivolumab, (Bristol-Myers Squibb), Pembrolizuma (Meb rck & Co), Pidilizuma (CureTeb ch), MEDI0680 (Medimmune) REGN2810, (Regeneron), TSR-042 (Tesaro) PF-, 06801591 (Pfizer) BGB-A317, (Beigene) BGB-, 108 (Beigene) INCS, HR1210 (Incyte) or, AMP-224 (Amplimmune). id="p-12" id="p-12" id="p-12" id="p-12" id="p-12"
[0012] In a further aspect of teh invention the, PD-1 inhibit oris PDR001 (spartalizumab). id="p-13" id="p-13" id="p-13" id="p-13" id="p-13"
[0013] Pharmaceut combinaical tions of (i) dabrafeni orb, a pharmaceutically accepta saltble there of,Compound A, or a pharmaceutically accepta salble thert eof, and Compound C, or a pharmaceutic accallyepta saltble there of,or (ii) dabrafenib, or a pharmaceutic acceptaally sablelt there of,Compound A, or a pharmaceutic accallyepta sablelt thereof, and a PD-1 inhibit orsuch as Spartalizumab will, also be referre to dherein as a "combinat ionof the invention". id="p-14" id="p-14" id="p-14" id="p-14" id="p-14"
[0014] There is provide a dcombinat ionof the invention for use in the treatment of cancer, e.g for use in a cance whichr is selected from brea stcancer, cholangiocarc inoma, salivar glandy cance colorr, ecta cancl er, melanoma, non-smal celll lung cancer, ovari an cance andr thyroid cancer. id="p-15" id="p-15" id="p-15" id="p-15" id="p-15"
[0015] There is provide a dpharmaceutic combinaal tion of (i) dabrafenib, or a pharmaceutic acceptaally sablelt there of,Compound A, or a pharmaceutic accallyepta sablelt thereof, and Compound C, or a pharmaceutic acceptaally saltble there of,or (ii) dabrafeni orb, a pharmaceutic acceptaally saltble there of,Compound A, or a pharmaceutic accallyeptab le salt thereof, and a PD-1 inhibit orsuch as spartaluzima e.gb, for use in a cance whichr is 5WO 2021/171260 PCT/IB2021/051641 selected from breas canct er, cholangiocarcinoma salivar glan, y cancd er, colorecta canlcer , melanoma, non-smal celll lung cancer, ovari ancanc erand thyroid cancer. id="p-16" id="p-16" id="p-16" id="p-16" id="p-16"
[0016] There is also provided a combinati ofon (i) dabrafeni orb, a pharmaceutically accepta saltble there of,Compound A, or a pharmaceutically accepta salble thert eof, and Compound C, or a pharmaceutic acceptaally saltble there of,or (ii) dabrafenib, or a pharmaceutic acceptaally sablelt there of,Compound A, or a pharmaceutic accallyepta sablelt there of,and a PD-1 inhibit orsuch as Spartalizumab for use in the treatment of colore ctal cance (whicr hincludes advanc ored metastsati colorec ctalcancer) which is BRAF gain of function or BRAFV600E/D/K mutants. id="p-17" id="p-17" id="p-17" id="p-17" id="p-17"
[0017] Also provid edherei isn a combination of the invention for use in the treatment of colore ctalcance (whicr hinclud esadvanced or metasts aticcolore ctalcancer which) is BRAF gain of function or BRAFV600E/D/K mutants. id="p-18" id="p-18" id="p-18" id="p-18" id="p-18"
[0018] In another embodiment of the combinat ionof the invention, dabrafenib, or a pharmaceutic acceptaally sablelt there of,Compound A, or a pharmaceutic accallyepta sablelt thereof, and Compound C, or a pharmaceutica accllyepta saltble there of,and are in the same formulation. id="p-19" id="p-19" id="p-19" id="p-19" id="p-19"
[0019] In another embodime ofnt the combinat ionof the invention, dabrafenib, or a pharmaceutic acceptaally sablelt there of,Compound A, or a pharmaceutic accallyepta sablelt thereof, and Compound C, or a pharmaceutica accllyepta saltble there of,are in separate formulations. id="p-20" id="p-20" id="p-20" id="p-20" id="p-20"
[0020] In another embodiment, the combination of the invention is for simultaneous or sequential (in any order) administration. id="p-21" id="p-21" id="p-21" id="p-21" id="p-21"
[0021] In another embodiment, the prese ntinvention provides a method for treating cance inr a subject in need there comprof isi ngadministerin to theg subject a therapeutically effective amount of the combinati ofon the invention. id="p-22" id="p-22" id="p-22" id="p-22" id="p-22"
[0022] In a furthe embodimr ent of the method, the cance isr selected from breas t cancer, cholangiocarcinoma salivary gland, cance colorectr, cancal er, melanoma, non-small cell lung cance ovarr, ian cance andr thyroid cancer. id="p-23" id="p-23" id="p-23" id="p-23" id="p-23"
[0023] In a furthe embodiment,r the prese ntinvention provides a combinat ionof the invention for use in the manufactur of ae medicament for treating a cancer selected from 6WO 2021/171260 PCT/IB2021/051641 brea stcancer, cholangiocarcin saomalivary ,gland cancer, colorect cancal er, melanoma non-, smal celll lung cancer, ovaria cancen andr thyroid cancer. id="p-24" id="p-24" id="p-24" id="p-24" id="p-24"
[0024] In another embodiment there is provided a pharmaceutic composial tion or commercial package (e.g. a kit-of-par comprts) isi theng combinat ionof the invention. id="p-25" id="p-25" id="p-25" id="p-25" id="p-25"
[0025] In a furthe embodiment,r the pharmaceutic composial tion furthe comprisr es one or more pharmaceutic acceptaally excible pients.
BRIEF DESCRIPTION OF THE DRAWINGS id="p-26" id="p-26" id="p-26" id="p-26" id="p-26"
[0026] Figure 1: Mice were randomized into treatment groups on Day 26 following HT29 tumor cel impll antati Treatmon. ents were initiated on Day 26 and continue untild Day 39 post tumor cel impll antati Tumoron. dimensions and body weights were collected at the time of randomization and twic weee kly therea fterfor the study duration. Tumor volumes (A) or perce nt body weight change (B) from initial of treatment groups vs. days post randomizat areion graphed.
Significa diffent renc fores tumor volume change were calculated using One-Way Analysis of variance (ANOVA) Tukey’s multiple comparison tes ont Day 39 with N=9 mice per group (p<0.05, for Dabrafenib+Compoun A+trd ameti nibtreated group versus vehicle, single agents and double combinations). id="p-27" id="p-27" id="p-27" id="p-27" id="p-27"
[0027] Figure 2: Mice were randomize intod treatme groupnt ons Day 28 followi ng HT29 tumor cel impll antati Treatmon. ents were initiated on Day 28 and continue untild Day 52 post tumor cel impll antati Tumoron. dimensions and body weights were collecte at thed tim eof randomization and twic weee kly therea fterfor the study duration. Tumor volumes (A) or perce nt body weight change (B) from initial of treatment groups vs. days post randomizat areion graphed.
Significa diffent renc werees calculated using One-Way Analysis of variance (ANOVA) Tukey’s multiple comparison test on Day 52 with N=7 mice per group, except untreated control group with n=4 (p<0.0001, for both combinations treated groups versus non treated controls). id="p-28" id="p-28" id="p-28" id="p-28" id="p-28"
[0028] Figure 3: Mice were randomized into treatment groups on Day 12 followi ng HCOX1329 tumor implantat ion.Treatments were initiated on Day 12 and continue untild Day 38 (vehicle), Day 62 (dabrafenib+ Compound A+trametinib or ),Day 67 (dabrafenib+trametinib and dabrafenib+trametinib+tcet postuxima tumorb) implantat ion.Tumor dimensions and body weights were collected at the tim eof randomization and twice weekl thereay fterfor the study 7WO 2021/171260 PCT/IB2021/051641 duration. Tumor volume (A)s or perce ntbody weight change (B) from initial of treatment group s vs. days post randomiza tionare graphed. Significa diffnt erenc werees calculated using One-Way Analys ofis variance (ANOVA) Tukey’s multiple comparison test on Day 38 with N=5 mice per group, except dabrafenib+Compound A+trametinib group with n=4 (p 0.005 for dabrafeni b +Compound A+trametinib vs dabrafenib+trame andtinib p=0.04, for dabrafenib + Compound A + tramet inibvs dabrafenib+trametinib+cetiximab).
DESCRIPTION id="p-29" id="p-29" id="p-29" id="p-29" id="p-29"
[0029] The general term useds hereinbefore and hereinafte prefrerab havely within the context of this disclos urethe followi meang nings, unless otherwise indicated, where more general terms whereeve usedr may, independently of eac hother, be replaced by more specifi c definitions or remain, thus defining more detailed embodiments of the invention: id="p-30" id="p-30" id="p-30" id="p-30" id="p-30"
[0030] "Dabrafenib" is N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tert-butyl)thiazo l-4-yl)-2- fluorophenyl)-2,6-difluorobenzenes aulfonam selecti inhibitorveide, of mutated BRAF at V600 capable of inhibiting BRAF(V600E), BRAF(V600K) and BRAF(V600G) mutations (als, oknown as: N-{3-[5-(2-Amino-4-pyrimidinyl)- 1,1 -dime2-( thylethyl)-1,3-thiazol-4-yl] -2- fluorophenyl}-2,6-difluorobenzenesulfonam Tafinlar &®;ide; N-{3[5-(2-Amino-4- pyrimidinyl)-2 1,1 -(-dimethylethyl)-1,3 -thiazol-4-yl] -2-fluorophenyl} -2,6 difluorobenzene sulfonamide, methanesulfonat salt).e id="p-31" id="p-31" id="p-31" id="p-31" id="p-31"
[0031] "Cetuximab" is an epiderm growthal factor receptor (EGFR) inhibitor used for the treatment of metastat colorectic canceal metasr, tati non-smalc celll lung canc erand head and neck cancer. Cetuximab is an epiderma growthl factor receptor-targetedlgGl monoclo nal antibody that is approved for use in combinat ionwit hirinotecan or as monotherapy in the treatment of metastati CRC.c Cetuximab is a chimeric (mouse/human) monoclonal antibody given by intravenous infusion. id="p-32" id="p-32" id="p-32" id="p-32" id="p-32"
[0032] "Compound A" is an inhibitor of extracellular signal-regulat kinasesed (ERK) 1/2. "Compound A" is 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyr azin-2- yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-f A luorobenzamide. particularly prefer redsalt of Compound A is the hydrochloride salt thereof. 8WO 2021/171260 PCT/IB2021/051641 id="p-33" id="p-33" id="p-33" id="p-33" id="p-33"
[0033] "Compound C", N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4- yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotina is an ATP compemide,titi inhibitorve of the BRAF and CRAF protei kinasn es. id="p-34" id="p-34" id="p-34" id="p-34" id="p-34"
[0034] The term PD-1 inhibitor includes PDR001. PDR001 is also known as spartalizumab, an anti-PD- 1antibody molecule described in US 2015/0210769, published on July , 2015, entitled "Antibody Molecules to PD-1 and Uses Thereof," incorporate by referend ince its entirety. id="p-35" id="p-35" id="p-35" id="p-35" id="p-35"
[0035] Further anti-PD-1 antibody molecul includees the following: id="p-36" id="p-36" id="p-36" id="p-36" id="p-36"
[0036] Nivoluma (Brisb tol-Mye Squibb),rs also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®. Nivolumab (clone 5C4) and other anti-PD -1antibodie ares disclose in dUS 8,008,449 and WO 2006/121168, incorpora byted refere ncein their entirety; id="p-37" id="p-37" id="p-37" id="p-37" id="p-37"
[0037] Pembrolizuma (Mercb k& Co), als knowno as Lambrolizuma MK-3475,b, MK03475, SCH-900475, or KEYTRUDA@. Pembrolizuma andb other anti-PD-1 antibodie ares disclose in d Hamid, O. et al. (2013) Mew England Journal ofMedi cine 369 (2): 134-44, US 8,354,509, and WO 2009/114335, incorpor atedby reference in thei entirr ety; id="p-38" id="p-38" id="p-38" id="p-38" id="p-38"
[0038] Pidilizumab (CureTech), als oknown as CT-011. Pidilizumab and other anti-PD-1 antibodie ares disclose ind Rosenblatt J. etal., (2 Oil) J Immunotherapy 34(5): 409-18, US 7,695,715, US 7,332,582, and US 8,686,119, incorpor atedby reference in their entirety; id="p-39" id="p-39" id="p-39" id="p-39" id="p-39"
[0039] MEDI0680 (Medimmune) als, knowno as AMP-514. MEDI0680 and other anti-PD-1 antibodie ares disclose ind US 9,205,148 and WO 2012/145493, incorpora byted refere ncein their entirety; id="p-40" id="p-40" id="p-40" id="p-40" id="p-40"
[0040] AMP-224 (B7-DCIg (Amplimmune), e.g., disclos ined WO 2010/027827 and WO 2011/066342, incorpor atedby reference in thei entirr ety; id="p-41" id="p-41" id="p-41" id="p-41" id="p-41"
[0041] REGN2810 (Regeneron); PF-06801591 (Pfizer) BGB-A; 317 orBGB-108 (Beigene); INCSHR1210 (Incyte) als, knowno as INCSHR01210 or SHR-1210; TSR-042 (Tesaro) als, knowno as ANB011; and further known anti-PD-1 antibodie includings those described, e.g., in WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727, incorpora byted refere ncein their entirety. id="p-42" id="p-42" id="p-42" id="p-42" id="p-42"
[0042] The term "subject" or "patient" as used herein is intende tod include animals, which are capable of suffering from or afflict withed a cance orr any disorder involving, 9WO 2021/171260 PCT/IB2021/051641 direct orly indirectl a cancer.y, Example ofs subjects include mammals, e.g., humans, apes , monkeys, dogs, cows, horses, pigs ,sheep, goats cat, s,mice ,rabbits, rats, and transgenic non- huma nanimal Ins. an embodiment, the subject is a human, e.g., a huma nsuffering from at, ris kof suffering from, or potentially capable of suffering from cancers. id="p-43" id="p-43" id="p-43" id="p-43" id="p-43"
[0043] The term "treat"ing or "treatment" as used herein compris aes treatme nt relieving, reducing or alleviat ating least one symptom in a subjec ort effect inga delay of progress ofion a disease. For exampl e,treatment can be the diminishmen of onet or severa l symptoms of a disorder or complete eradicat ofion a disorder, such as cancer. Withi nthe meaning of the prese ntdisclosu there, term "treat" als odenotes to arre st,dela they onset (i.e., the perio priord to clinical manifesta tionof a diseas e)and/or reduce the ris kof developing or worsening a disease. id="p-44" id="p-44" id="p-44" id="p-44" id="p-44"
[0044] The terms "comprising" and "including" are used herein in their open-ende d and non-limit ingsense unless otherwis noted.e id="p-45" id="p-45" id="p-45" id="p-45" id="p-45"
[0045] The terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the following claim s)are to be construed to cover both the singular and the plura unlesl, otherwises indicated herein or clearl y contradic byted conte xt.Wher thee plural form is used for compounds, salts, and the like, this is take ton mean also a single compound, salt, or the like. id="p-46" id="p-46" id="p-46" id="p-46" id="p-46"
[0046] By "a combination" or "in combinat ionwith" or "co-administr withation" and such like, it is not intende tod imply that the thera orpy the therapeuti agentsc must be physically mixed or administer at edthe same time and/o formular forted delivery together, although these methods of delivery are within the scope describe hereid n.A therapeuti agenc t in these combinations can be administered concurrent witlyh, prior to, or subseque ntto, one or more othe additionar theral pies or therapeutic agents. The therapeuti agentsc or therapeutic protocol can be administer ined any order In. general, eac hagent will be administer at eda dose and/or on a time schedule determined for that agent. It will furthe ber apprecia thatted the additional therapeuti agentc utilize ind this combinat ionmay be administer togethered in a single composition or administer separaed tely in differ entcompositions. In general, it is expected that additional therapeutic agents utilized in combination be utilize atd levels that do 10WO 2021/171260 PCT/IB2021/051641 not exceed the leve lsat which they are utilize individd ually In some. embodiments, the level s utilized in combinati willon be lower than those utilize asd single-agent therapeutics. id="p-47" id="p-47" id="p-47" id="p-47" id="p-47"
[0047] When describing a dosage or dose herei asn ‘about’ a specified amount the, actual dosage or dose can vary by up to 10%, e.g. 5%, from the stated amount: this usag eof ‘about’ recogniz thates the precis amounte in a given dose or dosage form may differ slight ly from an intended amount for various reasons without materially affect ingthe in vivo effec oft the administered compound. The skilled person will understan thatd wher ae dose or dosage of a therapeuti compouc nd is quoted herein, that amount refe rsto the amount of the therapeuti compoc und in its free form or unsolva tedform. id="p-48" id="p-48" id="p-48" id="p-48" id="p-48"
[0048] The phras "therapeuticae lly-effec amount"tive as used herei mean ns that amount of a compound, material, or composition comprisin a gcompound of the present invention which is effective for produci ngsome desire therad peutic effect in at least a sub- population of cel lsin an anima (inclul ding a human) at a reasonable benefit/ri ratiosk applicable to any medic altreatment. id="p-49" id="p-49" id="p-49" id="p-49" id="p-49"
[0049] The phras "pharmae ceutica accllyeptable" is employe hereind to refe tor those compounds, materia compositions,ls, and/o dosar ge forms which are, within the scope of sound medic aljudgment, suitable for use in contac witht the tissues of human beings and animals without excessive toxicity, irritation, aller gicresponse or ,othe problemr or complicat commion, ensurate wit ha reasonable benefit/risk ratio. id="p-50" id="p-50" id="p-50" id="p-50" id="p-50"
[0050] The combinations of the invention, dabrafeni compoub, nd A and compound C or spartalizumab, is also intende tod repres entunlabeled forms as wel asl isotopically labeled forms of the compounds Isotopic. ally labeled compounds have one or more atom replas ced by an atom having a selected atom icmass or mass number. Examples of isotope thats can be incorpora intoted dabrafeni compoundb, A and Compound C or spartalizumab include isotopes of hydroge carbon,n, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, nC, 13C, 14c, 15N, 18F 31p, 32p, 35s, 36Cl, 123I, 124I, 125I respectively. The invention includ esisotopical labely led dabrafeni compoub, nd A and compound C or spartalizumab, for example into which radioact isotopes,ive such as 3H and 14C, or non-radioact isotopeive s, such as 2H and 13C, are present. Isotopically labelled dabrafeni compoub, nd A and compound C or spartalizumab are useful in metabolic studie (withs 14C), reacti kineton icstudie (wits h, 11WO 2021/171260 PCT/IB2021/051641 for exampl 2eH or 3H), detectio or nimaging techniqu suches, as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissu edistribution assays, or in radioact treatmentive of patients. In particular, dabrafeni compob, und A or compound C or spartalizumab labeled with 18F may be particularly desirabl fore PET or SPECT studies Isotopically-. labeled compounds of the invention can generally be prepared by conventional techniques known to those skille ind the art or by processes analogous to those describe ind the accompanying Example usings appropri ateisotopically-labele reagents.d id="p-51" id="p-51" id="p-51" id="p-51" id="p-51"
[0051] Further subst, ituti witon hheavie isotopes,r particularly deuterium (i.e., 2H or D) may afford certa therapeutiin advantagesc result ingfrom great metaer bolic stability, for example increas ined vivo half-l orife reduced dosage requireme ornts an improvement in therapeuti index.c It is understood that deuterium in this context is regarded as a substitue nt of eithe dabrar feni compob, und A or compound C or spartalizumab. The concentrati of on such a heavie isotopr spece, ifica deuterium,lly may be defined by the isotopi enrichmc ent factor The. term "isotopic enrichm entfactor" as used herein means the ratio between the isotopic abundanc ande the natural abundance of a specifie isotope.d If a substituent dabrafeni compob, und A or compound C or spartalizumab is denoted deuterium, such compound has an isotopic enrichment factor for eac hdesigna teddeuteri umatom of at lea st 3500 (52.5% deuteri umincorporati at eaonch designa teddeuteri umatom), at leas 4000t (60% deuteri umincorporatio at leasn), 4500t (67.5% deuteri umincorporation) at lea, st5000 (75% deuteri umincorporatio at leasn), 5500t (82.5% deuteri umincorporation) at lea, st6000 (90% deuteri umincorporatio at leasn), 6333.3t (95% deuteri umincorporation) at lea, st6466.7 (97% deuteri umincorporatio at leasn), 6600t (99% deuteri umincorporation), or at leas 6633.3t (99.5% deuteri umincorporation).
Description of Preferr Embodimed ents id="p-52" id="p-52" id="p-52" id="p-52" id="p-52"
[0052] Dabrafenib is an orall bioavaiy lable sma llmolecule with RAF inhibitory activity. Compound A is an orall bioavaiy lable smal molecl ule wit hERK inhibitory activi ty.
It is an inhibitor of extracellular signal-regulat kinaseed 1 sand 2 (ERK 1/2). Compound C is an orally bioavaila smalble molel cule wit hB/C-RAF inhibitory activi ty.Spartalizumab is a 12WO 2021/171260 PCT/IB2021/051641 high-affinit ligay, nd-blocki humanizedng, anti-program death-med1 (PD-1) IgG4 antibody that blocks the bindin gof Programmed death-ligand 1 (PD-L1) and programmed death-ligan d 2 (PD-L2) to PD-1. id="p-53" id="p-53" id="p-53" id="p-53" id="p-53"
[0053] In one embodiment, wit hrespect to the pharmaceut combiical nati ofon the invention, is a pharmaceutic combinaal tion comprising: N-(3-(5-(2-aminopyrimidin-4-yl)-2- (tert-butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenes (dabrafenib),ulfonamide or a pharmaceutic acceptaally sablelt thereof; 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)- 2-fluorobenzamide (compound A), or a pharmaceutic accallyepta saltble thereof and; N-(3-(2- (2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-( trifluoromethyl)- isonicotinami (compoundde C), or a pharmaceutic accallyepta saltble thereof. id="p-54" id="p-54" id="p-54" id="p-54" id="p-54"
[0054] In a furthe embodiment,r N-(3-(5-(2-aminopyrimidin-4-yl)-2-( tert- butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenz (dabrafeenesulfnib),onamide or a pharmaceutic acceptaally sablelt there of,4-(3-amino-6-((lS,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)- 2-fluorobenzamide (compound A), or a pharmaceutic accallyepta saltble there of,and N-(3-(2- (2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-( trifluoromethyl)- isonicotinami (compoundde C), or a pharmaceutic accallyepta saltble there of,are administered separately, simultaneously or sequentially, in any order. id="p-55" id="p-55" id="p-55" id="p-55" id="p-55"
[0055] In a furthe embodiment,r the pharmaceutic combinaal tion is for oral administration. id="p-56" id="p-56" id="p-56" id="p-56" id="p-56"
[0056] In a furthe embodr iment of the pharmaceut combiical nation N-(,3-(5-(2- aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2-f luorophenyl)-2,6- difluorobenzenesulfonamide (dabrafenib) is in an oral dosage form. id="p-57" id="p-57" id="p-57" id="p-57" id="p-57"
[0057] In a furthe embodr iment of the pharmaceut combiical nation 4-(3-am, ino-6- ((lS,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fl uorophenyl)- 2-(methylamino)ethyl)-2-fluorobenzamide (compound A) is in an oral dosage form. id="p-58" id="p-58" id="p-58" id="p-58" id="p-58"
[0058] In a furthe embodr iment of the pharmaceut combiical nation N-(,3-(2-(2- hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trif luoromethyl)- isonicotinami (compoundde C) is in an oral dosage form. 13WO 2021/171260 PCT/IB2021/051641 id="p-59" id="p-59" id="p-59" id="p-59" id="p-59"
[0059] In another embodiment is a pharmaceuti compositioncal or a commercia l package comprisi theng pharmaceut combinaical tion (as described in any of the embodiments above) and at leas onet pharmaceutic acceptaally carble rier. id="p-60" id="p-60" id="p-60" id="p-60" id="p-60"
[0060] In another embodime isnt a pharmaceutic combial nati (ason describe ind any of the embodiments above) or the pharmaceuti composical tion or the commerci packageal (as describe ind the embodiments above) for use in the treatment of cancer. id="p-61" id="p-61" id="p-61" id="p-61" id="p-61"
[0061] In a furthe embodr imen thet, cance isr selected from brea stcancer, cholangiocarc inomacolorect, canceal (CRC),r melanoma, non-small cell lung cancer, ovarian cance andr thyroid cancer. id="p-62" id="p-62" id="p-62" id="p-62" id="p-62"
[0062] In a furthe embodiment,r the cance isr advanced or metastati colorc ect al cancer. id="p-63" id="p-63" id="p-63" id="p-63" id="p-63"
[0063] In a furthe embodiment,r the cance isr BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC. id="p-64" id="p-64" id="p-64" id="p-64" id="p-64"
[0064] In another embodime isnt a use of the pharmaceutic combinaal tion accordi ng to any of the above embodiments or the pharmaceutic composial tion or commerci packal age according to the above embodiments for the manufactur of ae medicament for the treatment of cancer. id="p-65" id="p-65" id="p-65" id="p-65" id="p-65"
[0065] In a furthe embodr imen thet, cance isr selected from brea stcancer, cholangiocarcinoma colorect, cancal er, melanoma, non-smal celll lung cancer, ovarian canc er and thyroid cancer, optional wherely thein cancer is advanced or metastati colorectc cancer,al optional whereinly the cance isr BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC. id="p-66" id="p-66" id="p-66" id="p-66" id="p-66"
[0066] In another embodiment is a method of treat inga cance selecr ted from breas t cancer, cholangiocarcinoma colorecta, cancl er, melanoma, non-small cell lung cancer, ovarian cance andr thyroid cance comprir sing administrat to inga patient in need thereof a pharmaceutic combinaal tion or commerci packageal accordi tong any one of the above embodiemnts or the pharmaceut compositionical according to the above embodiments. id="p-67" id="p-67" id="p-67" id="p-67" id="p-67"
[0067] In a furthe embodiment,r the colorect canceal isr advanced or metastati c colore ctalcancer. id="p-68" id="p-68" id="p-68" id="p-68" id="p-68"
[0068] In a furthe embodiment,r the colorect canceal isr BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC. 14WO 2021/171260 PCT/IB2021/051641 id="p-69" id="p-69" id="p-69" id="p-69" id="p-69"
[0069] In a furthe embodiment,r N-(3-(5-(2-aminopyrimidin-4-yl)-2-( tert- butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenz (dabrafenesulfenib) onamideis administer orallyed at a dose of about from about 1 to about 150 mg per day (for example, 1, 2, 5, 10, 50, 100 or 150 mg per day). id="p-70" id="p-70" id="p-70" id="p-70" id="p-70"
[0070] In a furthe embodiment,r N-(3-(5-(2-aminopyrimidin-4-yl)-2-( tert- butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenz (dabenesulfrafenib) onamideis administered orally at a dose of 75mg BID. id="p-71" id="p-71" id="p-71" id="p-71" id="p-71"
[0071] In a furthe embodiment,r 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)- 2-fluorobenzamide (compound A) is administered orall aty a dose of from about 50 to about 200 mg per day (for example, at a dose of about 50, 75, 100, 125, 150, 175 or 200 mg per day). id="p-72" id="p-72" id="p-72" id="p-72" id="p-72"
[0072] In a furthe embodiment,r 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)- 2-fluorobenzamide (compound A) is administered orall aty a dose of lOOmg QD. id="p-73" id="p-73" id="p-73" id="p-73" id="p-73"
[0073] In a furthe embodiment,r 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)- 2-fluorobenzamide (compound A) is administered orall aty a dose of 200mg QD. id="p-74" id="p-74" id="p-74" id="p-74" id="p-74"
[0074] In a furthe embodiment,r N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4- yl)-4-methylphenyl)-2-(trifluoromethyl)-is (compoundonicotinamide C) is adminstered orally at a dose of from about 100 mg per day, or 200 mg per day, or 300 mg per day to about 400 mg per day. id="p-75" id="p-75" id="p-75" id="p-75" id="p-75"
[0075] In a furthe embodiment,r N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyr idin-4- yl)-4-methylphenyl)-2-(trifluoromethyl)-is (compoundonicotinamide C) is adminstered orally at a dose of 200mg BID. id="p-76" id="p-76" id="p-76" id="p-76" id="p-76"
[0076] In one embodiment, wit hrespect to the pharmaceut combiical nati ofon the invention, is a pharmaceutic combinaal tion comprising: N-(3-(5-(2-aminopyrimidin-4-yl)-2- (tert-butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenes (dabrafenib),ulfonamide or a pharmaceutic acceptaally sablelt thereof; 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)- 15WO 2021/171260 PCT/IB2021/051641 2-fluorobenzamide (compound A), or a pharmaceutic accallyepta saltble thereof; and a PD-1 inhibitor or ,a pharmaceutica accllyepta salble thert eof. id="p-77" id="p-77" id="p-77" id="p-77" id="p-77"
[0077] In a furthe embodiment,r N-(3-(5-(2-aminopyrimidin-4-yl)-2-( tert- butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenz (dabrafeenesulfnib),onamide or a pharmaceutic acceptaally sablelt there of,4-(3-amino-6-((lS,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)- 2-fluorobenzamide (compound A), or a pharmaceutic accallyepta saltble there of,and a PD-1 inhibitor or ,a pharmaceutica accllyepta salble thert eof, are administer separed atel y, simultaneously or sequentially, in any order. id="p-78" id="p-78" id="p-78" id="p-78" id="p-78"
[0078] In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. id="p-79" id="p-79" id="p-79" id="p-79" id="p-79"
[0079] In a further embodime nt,the PD-1 inhibit oris an anti-PD -1antibody molecule as described in US 2015/0210769, published on July 30, 2015, entitled "Antibody Molecules to PD-1 and Uses Thereof," incorporat by edrefere ncein its entirety. In some embodiments, the anti-PD-1 antibody molecule is BAP049-Clone E or BAP049-Clone B. id="p-80" id="p-80" id="p-80" id="p-80" id="p-80"
[0080] In a further embodime nt,the anti-PD -1antibody molecul is eSpartalizuma b (PDR001). id="p-81" id="p-81" id="p-81" id="p-81" id="p-81"
[0081] In one embodiment, the anti-PD- 1antibody molecule comprise ats leas one,t two, three, four, five or six complement aritydetermining regions (CDRs) (or collective all ofly the CDRs) from a heavy and light chain variable region comprising an amin oacid sequence shown in Table 1 (e.g., from the heavy and light chain variable region sequences of BAP049-Clone- orE BAP049-Clone-B disclos ined Table 1), or encoded by a nucleotide sequence shown in Table 1.
In some embodiments, the CDRs are according to the Kaba definit tion (e.g. ,as set out in Table 1).
In some embodiments, the CDRs are according to the Chothia definition (e.g. ,as set out in Table 1). In some embodiments the ,CDRs are according to the combine CDRd definitions of both Kaba andt Chothia (e g., as set out in Table 1). In one embodiment, the combination of Kaba and t Chothia CDR of VH CDR1 compris thees amino acid sequence GYTFTTYWMH (SEQ ID NO: 541). In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three four,, five six, or more changes e.g.,, amino acid substitutions (e.g., conserva amintive o acid substitutions) or deletions rela, tive to an amino aci dsequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. 16WO 2021/171260 PCT/IB2021/051641 id="p-82" id="p-82" id="p-82" id="p-82" id="p-82"
[0082] In one embodiment, the anti-PD- 1antibody molecule comprise a sheavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 501, a VHCDR2 amin oacid sequenc ofe SEQ ID NO: 502, and a VHCDR3 amino acid sequence of SEQ ID NO: 503; and a light chai varian ble region (VL) comprising a VLCDR1 amin oaci d sequenc ofe SEQ ID NO: 510, a VLCDR2 amino acid sequenc ofe SEQ ID NO: 511, and a VLCDR3 amin oacid sequenc ofe SEQ ID NO: 512, each disclos ined Table 1. id="p-83" id="p-83" id="p-83" id="p-83" id="p-83"
[0083] In one embodiment the, antibody molecule comprise a sVH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, a VHCDR2 encoded by the nucleot idesequence of SEQ ID NO: 525, and a VHCDR3 encoded by the nucleot sequenceide of SEQ ID NO: 526; and a VL comprising a VLCDR1 encoded by the nucleotide sequenc ofe SEQ ID NO: 529, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 530, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 531, each disclos ined Table 1. id="p-84" id="p-84" id="p-84" id="p-84" id="p-84"
[0084] In one embodiment, the anti-PD- 1antibody molecule comprise a sVH comprising the amin oacid sequenc ofe SEQ ID NO: 506, or an amin oacid sequence at leas 85%,t 90%, 95%, or 99% identical or higher to SEQ ID NO: 506. In one embodiment, the anti-PD- 1antibody molecule comprise a sVL comprising the amino aci dsequence of SEQ ID NO: 520, or an amino acid sequence at leas 85%,t 90%, 95%, or 99% identica or lhigher to SEQ ID NO: 520. In one embodiment, the anti-PD- 1antibody molecule compris aes VL comprising the amino aci d sequenc ofe SEQ ID NO: 516, or an amino aci dsequence at leas 85%,t 90%, 95%, or 99% identica or lhigher to SEQ ID NO: 516. In one embodiment the, anti-PD- 1antibody molecule compris aes VH comprising the amin oaci dsequenc ofe SEQ ID NO: 506 and a VL comprising the amin oacid sequence of SEQ ID NO: 520. In one embodime nt,the anti-PD- 1antibody molecule compris aes VH comprising the amino aci dsequence of SEQ ID NO: 506 and a VL comprising the amino aci dsequence of SEQ ID NO: 516. id="p-85" id="p-85" id="p-85" id="p-85" id="p-85"
[0085] In one embodiment the, antibody molecule comprise a sVH encoded by the nucleot idesequence of SEQ ID NO: 507, or a nucleot sequenceide at leas 85%,t 90%, 95%, or 99% identical or higher to SEQ ID NO: 507. In one embodiment, the antibody molecule compris aes VL encoded by the nucleot idesequen ceof SEQ ID NO: 521 or 517, or a nucleotide sequenc ate leas 85%,t 90%, 95%, or 99% identica or lhigher to SEQ ID NO: 521 or 517. In one embodiment, the antibody molecule comprise a sVH encoded by the nucleot idesequenc ofe SEQ ID NO: 507 and a VL encoded by the nucleot sequenceide of SEQ ID NO: 521 or 517. 17WO 2021/171260 PCT/IB2021/051641 id="p-86" id="p-86" id="p-86" id="p-86" id="p-86"
[0086] In one embodiment, the anti-PD- 1antibody molecule comprise a sheavy chain comprising the amino aci dsequence of SEQ ID NO: 508, or an amino acid sequence at leas 85%,t 90%, 95%, or 99% identical or higher to SEQ ID NO: 508. In one embodiment, the anti-PD-1 antibody molecule compris aes light chain comprising the amin oaci dsequenc ofe SEQ ID NO: 522, or an amin oacid sequence at leas 85%,t 90%, 95%, or 99% identica or lhigher to SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprise a slight chai n comprising the amino acid sequence of SEQ ID NO: 518, or an amino aci dsequence at leas 85%,t 90%, 95%, or 99% identical or higher to SEQ ID NO: 518. In one embodiment, the anti-PD-1 antibody molecu comprisele a sheavy chain comprising the amin oacid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequenc ofe SEQ ID NO: 522. In one embodiment, the anti-PD- 1antibody molecule compris aes heavy chain comprising the amino acid sequenc ofe SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 518. id="p-87" id="p-87" id="p-87" id="p-87" id="p-87"
[0087] In one embodiment the, antibody molecule comprise a sheavy chai encodedn by the nucleotide sequence of SEQ ID NO: 509, or a nucleotide sequence at leas 85%,t 90%, 95%, or 99% identical or higher to SEQ ID NO: 509. In one embodiment, the antibody molecule compris aes light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519, or a nucleot idesequence at leas 85%,t 90%, 95%, or 99% identica or lhigher to SEQ ID NO: 523 or 519. In one embodiment, the antibody molecule compris aes heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleot idesequence of SEQ ID NO: 523 or 519. id="p-88" id="p-88" id="p-88" id="p-88" id="p-88"
[0088] The antibody molecules described herein can be made by vectors host, cells, and methods described in US 2015/0210769, incorporate by refd ere ncein its entirety.
Table 1. Amino acid and nucleotide sequenc ofes exemplar anti-y PD-1 antibody molecules BAP049-Clone-B HC SEQ ID N()^ HCDRI 'tywmh llEQIDN(^^ ™HCDR2™' 'nIYPGTGGSWdERFRN HCDR3 WTTGTGAY SEQ ID NO: 503 (Rabat) SEQ ID NO: 504 HCDR1 GYTFTTY (Chothia) SEQIDNO: 565 YPGTGG (Chothia) 18WO 2021/171260 PCT/IB2021/051641 SEQ ID NO: 503 HCDR3 WTTGTGAY (Chothia) SEQ ID NO: 506 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQ ATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTA YMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS DNAVH SEQ ID NO: 507 GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAA GCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCC AGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATC TACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTT AAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAG CACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGG ACACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCA CAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTG TCTAGC SEQ ID NO: 508 Heavy EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQ chain ATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTA YMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSA STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTC NVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKGLP S SIEKTISKAKGQPREPQVYTLPP SQEEMTKNQ V SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LG SEQ ID NO: 509 DNA GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAA heavy GCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG chain GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCC AGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATC TACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTT AAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAG CACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGG ACACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCA CAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTG TCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTG GCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCC 19WO 2021/171260 PCT/IB2021/051641 CTCGGCTGCCTGGTC A AGG ATTACTTCCCGG AGCCCGTG ACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGT GCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTA CTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCT GGGTACCAAGACCTACACTTGCAACGTGGACCACAAGC CTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAG TACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTC CTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCC AAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACA TGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGT GCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACA ACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCC ACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAG GACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTC CAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCT CGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTAT ACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCA AGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATC GGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGG AAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCA GACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGAT AAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTC TGTGATGCATGAAGCCCTGCACAACCACTACACTCAGA AGTCCCTGTCCCTCTCCCTGGGA BAPO^ SEQIDNO: 510 (Rabat) LCDR1 KSSQSLLDSGNQKNFLT SEQIDNO: 511 (Rabat) LCDR2 WASTRES LCDR3 QNDYSYPYT SEQIDNO: 512 (Rabat) SEQIDNO: 513 LCDR1 SQSLLDSGNQKNF (Chothia) SEQIDNO: 514 LCDR2 WAS (Chothia) ~SEQ1dn6?515 TcdrT™ "dysypy (Chothia) SEQIDNO: 516 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTW YQQRPGRAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISS LQPEDIATYYCQNDYSYPYTFGQGTKVEIK 20WO 2021/171260 PCT/IB2021/051641 GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTG SEQIDNO: 517 DNA VL AGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTAG TCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCT GACCTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGC TGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGC CCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCA CCTTCACTATCTCTAGCCTGCAGCCCGAGGATATCGCTA CCTACTACTGTCAGAACGACTATAGCTACCCCTACACCT TCGGTCAAGGCACTAAGGTCGAGATTAAG Light EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTW SEQIDNO: 518 chain YQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISS LQPEDIATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSRDSTYSLSSTLTLSRADYERHRVYACEVT HQGLSSPVTKSFNRGEC "CAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTG™ "8EQIDn675T9 "dna light AGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTAG chain TCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCT GACCTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGC TGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGC CCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCA CCTTCACTATCTCTAGCCTGCAGCCCGAGGATATCGCTA CCTACTACTGTCAGAACGACTATAGCTACCCCTACACCT TCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTG GCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAG CAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCT GAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGA AGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAG AGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAG CCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACG AGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAG GGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGG CGAGTGC BAP049-Clone-E HC TYWMH SEQ ID NO: 501 (Rabat) HCDR1 HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 502 (Rabat) "SEQ^DNO?^^ wffGfGAY "hcdrT" 21WO 2021/171260 PCT/IB2021/051641 GYTFTTY HCDRI SEQ ID NO: 504 (Chothia) SEQ ID NO: 505 HCDR2 YPGTGG (Chothi a) 'wffGTGAY '1eq7dno:563 HCDR3 (Chothia) SEQ ID NO: 506 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQ ATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTA YMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 507 DNAVH GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAA GCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCC AGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATC TACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTT AAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAG CACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGG ACACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCA CAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTG TCTAGC '1EQ^DNO:'508 Heavy evqlvqsgae^'kpgeslris^ chain ATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTA YMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSA STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTC NVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKGLP S SIEKTISKAKGQPREPQVYTLPP SQEEMTKNQ V SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LG SEQ ID NO: 509 DNA GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAA heavy GCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG chain GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCC AGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATC TACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTT AAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAG CACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGG 22WO 2021/171260 PCT/IB2021/051641 AC ACCGCCGTCTACTACTGCACTAGGTGGACTACCGGC A CAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTG TCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTG GCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCC CTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTG ACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGT GCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTA CTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCT GGGTACCAAGACCTACACTTGCAACGTGGACCACAAGC CTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAG TACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTC CTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCC AAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACA TGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGT GCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACA ACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCC ACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAG GACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTC CAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCT CGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTAT ACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCA AGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATC GGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGG AAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCA GACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGAT AAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTC TGTGATGCATGAAGCCCTGCACAACCACTACACTCAGA AGTCCCTGTCCCTCTCCCTGGGA BAP049-^ SEQ ID~N^ Tcdri Tssqslldsgnqknflt ‘lEOTONoTyLUKabaO™' "WASTRES TcdrT™ SEQIDNO: 512 (Rabat) LCDR3 QNDYSYPYT SEQIDNO: 513 LCDR1 SQSLLDSGNQKNF (Chothia) SEQIDNO: 514 TcDR2™" WAS (Chothia) SEQIDNO: 515 LCDR3 DYSYPY (Chothia) 23WO 2021/171260 PCT/IB2021/051641 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTW SEQ ID NO: 520 VL YQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISS LEAEDAATYYCQNDYSYPYTFGQGTKVEIK DNA \ii GAGATCGfCCTGACT^ SEQ ID NO: 521 AGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTAG TCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCT GACCTGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGAC TGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGC CCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCA CCTTCACTATCTCTAGCCTGGAAGCCGAGGACGCCGCTA CCTACTACTGTCAGAACGACTATAGCTACCCCTACACCT TCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 522 Light EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTW chain YQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISS LEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTRSFNRGEC "SEQIDN6i5^ "CAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTG™ "dna light AGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTAG chain TCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCT GACCTGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGAC TGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGC CCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCA CCTTCACTATCTCTAGCCTGGAAGCCGAGGACGCCGCTA CCTACTACTGTCAGAACGACTATAGCTACCCCTACACCT TCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTG GCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAG CAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCT GAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGA AGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAG AGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAG CCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACG AGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAG GGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGG CGAGTGC BAP049-Clone-B HC SEQ ID NO: 524 (Rabat) HCDR1 ACCTACTGGATGCAC 24WO 2021/171260 PCT/IB2021/051641 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAG SEQ ID NO: 525 (Rabat) HCDR2 AAGTTTAAGAAT SEQ ID NO: 526 (Rabat) HCDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 527 HCDR1 GGCTACACCTTCACTACCTAC (Chothia) SEQ ID NO: 528 HCDR2 TACCCCGGCACCGGCGGC (Chothia) "TGGACTACCGGCACAGGCGCCTAC "SEQIDn6^526 ™hcdrT™ (Chothia) BAP049-Clone-B LC SEQ ID NO: 529 (Rabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAA GAACTTCCTGACC SEQ ID NO: 530 (Rabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 531 (Rabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 532 LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTT (Chothi a) C SEQID~N^ "lCDR2 TGGGCCTCT (Chothia) SEQ ID NO: 534 LCDR3 GACTATAGCTACCCCTAC (Chothia) BAP049-Clone-E HC SEQ ID NO: 524 (Rabat) HCDR1 ACCTACTGGATGCAC HCDR2 SEQ ID NO: 525 (Rabat) AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAG AAGTTTAAGAAT ■lEQroN67526 (KabaO™ ״TGGACTACCGGCACAGGCGCCTAC HCDR3 SEQ ID NO: 527 HCDR1 GGCTACACCTTCACTACCTAC (Chothia) "SEQIDN075^ "hCDR2 "tACCCCGGCACCGGCGGC (Chothia) SEQ ID NO: 526 HCDR3 TGGACTACCGGCACAGGCGCCTAC (Chothia) BAPO^ liEQnyN(^^ ״AAAfCTAGTCAOT^ Tcdri GAACTTCCTGACC SEQ ID NO: 530 (Rabat ) LCDR2 TGGGCCTCTACTAGAGAATCA lEQroNO?«r^abatr" ״CAGAAC^ TcdrT™ 25WO 2021/171260 PCT/IB2021/051641 LCDRI SEQ ID NO: 532 AGTC AGTC ACTGCTGGATAGCGGTA ATC AGA AG AACTT (Chothia) C SEQ ID NO: 533 LCDR2 TGGGCCTCT (Chothi a) '1eqTdNO:'534 TcDR3 "gactatagctacccctac (Chothia) id="p-89" id="p-89" id="p-89" id="p-89" id="p-89"
[0089] In a furthe embodr iment of the pharmaceut combiical nation N-(,3-(5-(2- aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2-f luorophenyl)-2,6- difluorobenzenesulfonamide (dabrafenib) is in an oral dosage form. id="p-90" id="p-90" id="p-90" id="p-90" id="p-90"
[0090] In a furthe embodr iment of the pharmaceut combiical nation 4-(3-am, ino-6- ((lS,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fl uorophenyl)- 2-(methylamino)ethyl)-2-fluorobenzamide (compound A) is in an oral dosage form. id="p-91" id="p-91" id="p-91" id="p-91" id="p-91"
[0091] In another embodiment is a pharmaceuti compositioncal or a commercia l package comprisi theng pharmaceut combinaical tion (as described in any of the embodiments above) and at leas onet pharmaceutic acceptaally carble rier. id="p-92" id="p-92" id="p-92" id="p-92" id="p-92"
[0092] In another embodime isnt a pharmaceutic combial nati (ason describe ind any of the embodiments above) or the pharmaceuti composical tion or the commerci packageal (as describe ind the embodiments above) for use in the treatment of cancer. id="p-93" id="p-93" id="p-93" id="p-93" id="p-93"
[0093] In a furthe embodiment,r the canc eris selected from brea stcancer, cholangiocarc inomacolorect, canceal (CRC),r melanoma, non-small cell lung cancer, ovarian cance andr thyroid cancer. id="p-94" id="p-94" id="p-94" id="p-94" id="p-94"
[0094] In a furthe embodiment,r the cance isr advanced or metastati colorc ect al cancer. id="p-95" id="p-95" id="p-95" id="p-95" id="p-95"
[0095] In a furthe embodiment,r the cance isr BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC. id="p-96" id="p-96" id="p-96" id="p-96" id="p-96"
[0096] In another embodime isnt a use of the pharmaceutic combinaal tion accordi ng to any of the above embodiments or the pharmaceutic compositional or commercial package according to the above embodiments for the manufactur of ae medicame fornt the treatment of cancer. id="p-97" id="p-97" id="p-97" id="p-97" id="p-97"
[0097] In a furthe embodiment,r the cance isr selected from brea stcancer, cholangiocarcinoma colorect, cancal er, melanoma, non-smal celll lung cancer, ovarian canc er 26WO 2021/171260 PCT/IB2021/051641 and thyroid cancer, optional wherely thein cancer is advanced or metastati colorectc cancer,al optional whereinly the cance isr BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC. id="p-98" id="p-98" id="p-98" id="p-98" id="p-98"
[0098] In another embodiment is a method of treat inga cance selecr ted from breas t cancer, cholangiocarcin coloroma,ecta cancl er, melanoma, non-small cell lung cancer, ovarian cance andr thyroid cance comprr isin adminisg trati to ang patient in need thereof a pharmaceutic combinaal tion or commerci packageal accordi tong any one of the above embodiemnts or the pharmaceut compositionical according to the above embodiments. id="p-99" id="p-99" id="p-99" id="p-99" id="p-99"
[0099] In a furthe embodiment,r the colorect canceal isr advanced or metastati c colore ctalcancer. id="p-100" id="p-100" id="p-100" id="p-100" id="p-100"
[00100] In a furthe embodiment,r the colorect canceal isr BRAF gain of function CRC or BRAF V600E, V600D or V600K CRC. id="p-101" id="p-101" id="p-101" id="p-101" id="p-101"
[00101] In a furthe embodiment,r N-(3-(5-(2-aminopyrimidin-4-yl)-2- (tert- butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenz (dabenesulfrafenib) onamideis administer orallyed at a dose of about from about 1 to about 150 mg per day (for example, 1, 2, 5, 10, 50, 100 or 150 mg per day). id="p-102" id="p-102" id="p-102" id="p-102" id="p-102"
[00102] In a furthe embodiment,r 4-(3-amino-6-((lS,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-l-(3-bromo-5-fluorophenyl)-2- (methylamino)ethyl)- 2-fluorobenzamide (compound A) is administered orall aty a dose of from about 50 to about 200 mg per day (for example, at a dose of about 50, 75, 100, 125, 150, 175 or 200 mg per day). id="p-103" id="p-103" id="p-103" id="p-103" id="p-103"
[00103] In a further embodime nt,the PD-1 inhibit oris administe atred a dose of about 300- 400 mg. id="p-104" id="p-104" id="p-104" id="p-104" id="p-104"
[00104] In a further embodime nt,the PD-1 inhibit oris administe oncered every 3 week ors once every 4 weeks. id="p-105" id="p-105" id="p-105" id="p-105" id="p-105"
[00105] In another embodiment, the PD-1 inhibit oris administer at eda dose of about 300 mg once every 3 weeks. id="p-106" id="p-106" id="p-106" id="p-106" id="p-106"
[00106] In another embodiment, the PD-1 inhibitor is administer at eda dose of about 400 mg once every 4 weeks. 27WO 2021/171260 PCT/IB2021/051641 Pharmacology and Utility id="p-107" id="p-107" id="p-107" id="p-107" id="p-107"
[00107] The RAS/RAF/MEK/ERK or mitogen activated prote kinasein (MAPK) pathway is a key signaling casca dethat integrate upstrs eam cellular signals such, as from growth fact or receptor tyrosine kinases, to orchestr cellate proliferation, differentia andtion, surviv al.The MAPK signaling pathwa is yfrequently dysregulated in human cancers most, commonly throu gh mutation of members of the RAS famil ofy genes These. mutations promote the GTP-bound sta te resulting in RAS activity leading in turn to activat ofion RAF, MEK, and ERK proteins. RAS mutations are found in multiple cancer types, includi ngcolorectal, lung, and pancreatic cancers . id="p-108" id="p-108" id="p-108" id="p-108" id="p-108"
[00108] RAF (Rapidl Acceley rate Fibrosad rco isma) a serine-threonine prote kinasin e discove redas a retroviral oncogene The. RAF famil ofy proteins (ARAF, BRAF, CRAF) signal s just downstrea of mactivate RAS.d Activated GTP-bound RAS recruits cytosol inactiveic RAF monomer tos the plasma membra newhere RAF binds to GTP-RAS thereb promoty inghomo- and heterodimerizati of RAF.on The dimerization of RAF facilitates conformational changes that lead to catalyticall activatey RAF.d Activat RAFed dimer phosphorylates and activate MEK1/2 (also known as mitogen-acti vateproteind kinas e)proteins which, subsequently phosphoryl andate activate extracel lulasignal-r regula kinaseted (ERK1/2).s ERKs phosphory latea varie ofty substrat includies, ngmultiple transcripti facontors, thereby regulating several key cellular activities including, proliferation, metabolism, migration, and survival. The role of ERK1/2 in cancer is of special interes becaust activate mutationsing upstream of ERK1/2 in its signaling casca deare believed to be responsib forle more than half of all cancers. id="p-109" id="p-109" id="p-109" id="p-109" id="p-109"
[00109] Dysregulated activation at any step in the MAPK pathway contribut toes tumorigenesis. Activati BRAFng mutatio canns be found in approximately 7% of cancers with, V600E accounting for great thaner 90% of observe mutationsd in BRAF. The V600E mutati on encode a svaline to glutamic acid substitution that exposes the activ sitee of BRAF, enabli ngits constitut activative asion monome orrs dimers independent of RAS. Inhibitors of activ RAF,e such as vemurafenib dabra, feni andb, encorafe havenib, demonstr ateddrama ticactivi inty BRAF V600E metastatic melanoma with overa respll onse rates (ORR) of 50-70%. The succe ssof these inhibito inrs V600E melanoma derive froms the ability to bind to and inhibi thet mutant monomeric form of RAF that is the oncogenic drive inr cancer cells. However in ,cance cellsr that expres wild-types BRAF, or in the normal cells of patient withs V600E driven cancers, inhibito suchrs as vemurafenib paradoxical actilyvate RAF signali ng.The complexity of MAPK 28WO 2021/171260 PCT/IB2021/051641 pathway signal ingin the presence of monomeric RAF inhibitors is highlighted in patients whose BRAF V600E-dependent melanoma cell dies while normal epiderma cellsl containi wild-typeng BRAF hyperprolifera Thiste. paradoxica activatl ofion RAF in wild-type cells is precipita byted the inhibitor’s binding to one protomer of a RAF dimer. This leads to a conformationa changel that prevents inhibitor binding to the second protomer, and transactivati of theon second RAF protomer of the dimer ensues Inhibiti. on at sequential nodes of the MAPK pathway with RAF- and MEK-direct combinaed tion therapy attenuat RAFes dimer signaling in normal cells thereby, improving safe tyand clinical activity in metastatic BRAF V600 melanoma. id="p-110" id="p-110" id="p-110" id="p-110" id="p-110"
[00110] Single-ag RAFent inhibitors or combination RAF/MEK inhibition in BRAF V600E colorec cancertal (CRC) demonstrate minimal activity; clinical benefit is limited compare tod the activity seen in melanoma. Intrinsic and acquir edresista nceto RAF inhibitors and MEK inhibitors devel opat multiple level ofs the MAPK pathway. The complexities of signaling feedbac andk alternate pathways that circumvent BRAF inhibition are centr toal the challenge of target actiing vated BRAF in CRC. Under physiologic conditions, activate MAPKd signaling through mutant BRAF leads to ERK-depende negativent feedback on signals generated through activate RAS.d Intrins resiic stance to RAF inhibition manife stsbecause drugs such as vemurafeni or bdabrafenib effective inhibitly BRAF V600E signaling through MEK to ERK; howeve thisr, in turn release ERK-dependes negatnt ivefeedback into RAS signaling. Therefor e, upstream signal ares able to activate RAS, leading to the induction of BRAF V600E and wild-type homo- and heterodimers Because. agents such as dabrafeni andb vemurafenib inhibit V600E activated monome inrs BRAF-dependent CRC cells RAS-st, imulated RAF dimer signal ingis unopposed, leading to ERK reactivation to a great degreeer than is seen in BRAF V600E melanoma, and thus limitin theg effectivenes of therapys in CRC. [00 111] Under the pressure of BRAF and MEK inhibition in BRAF V600E CRC, acquir ed resistan quicklyce develo ps.For instance, in an analysi ofs nine tumor sample froms eight patients experiencing diseas progrese sion afte MAPr K inhibition, geneti altc erat leaionsding to MAPK reactivatio weren uncovered. These include actid vating mutation in sKRAS orNRAS, amplifica tionof wild-type (WT) NRAS or KRAS or mutant BRAF V600E, and an intrageni c deletion in BRAF V600E. Acquired genetic alterations have also been reported, leading to reactiva oftion ERK signali inng the fac ofe MAPK inhibito rs.Acquired resista ncemay also aris e through complementary signali inng the tumor microenvironment. 29WO 2021/171260 PCT/IB2021/051641 id="p-112" id="p-112" id="p-112" id="p-112" id="p-112"
[00112] Though previous therapeutic approaches to SF4F-mutant CRC have focused on chemother and/orapy targe tedtherapy, there is als oa role for immunotherapy. During tumorigenesi cancers, cells exploit immune checkpoint pathways to avoid detecti byon the adaptive immune system Monoclonal. antibody (mAb) inhibitors of the Programmed Cell Death Protein-1 (PD-1) and Programmed Death-Liga 1nd (PD-L1) immunologi checalckpoints have demonstrate signifd icant antitumor activi inty patient withs various solid tumors. PD-1 is a particular imporly tant immunologic targetal with, inhibitors such as pembrolizumab and nivolumab demonstrating single-agent activity in melanoma non-small, cel lungl carcinoma (NSCLC), and other solid tumors. id="p-113" id="p-113" id="p-113" id="p-113" id="p-113"
[00113] CRC, howeve isr, genera unreslly pons toive PD-1 blockade with the exception of tumors possessing micro satellite instability There. is, howeve rationalr, for ethe use of sma ll molecule inhibitors to modulate the immune response. The same therapi thates inhibi genetit c dependencie on sthe MAPK pathwa iny cancer cells inhibit signali casng cade in simmun ecells.
For instanc prece, linic studieal demonstrs atedthat MAPK pathway inhibito rs,such as BRAF and MEK inhibitors, could improve lymphocyte homing and functi onby increasi tumorng infiltrati ng lymphocytes in tumors. id="p-114" id="p-114" id="p-114" id="p-114" id="p-114"
[00114] Therefore, RAF and MEK inhibitors may modulate the immun eresponse to tumors, and the combination of such agents with checkpoint blocka mayde increase the susceptibil ofity "immune cold" tumor suchs as CRC to PD-1 inhibition. Furthermore, approximately 20% of SF4F-mutant CRCs are characteri byzed geneti micrc sateo llite instabilit y (MSI-H: microsatelli instteability-high). In MSI-H CRC, irrespecti ofve BRAF geneti stac tus, single-agent anti-PD- ther1 apy has been associated with response rates of 30-50%. Furthermore, targe tedMAPK inhibition in tumor immun ecells may complement the mechanism of action of anti-PD- 1antibodie in smicrosatel stablelite and mismatch-re defipaircient CRC, there by potential increly asi anti-cng ancer immunomoduclation. id="p-115" id="p-115" id="p-115" id="p-115" id="p-115"
[00115] Lung cance isr a common type of cance thatr affect mens and women around the globe. NSCLC is the most common type (roughly 85%) of lung cance withr approximat 70%ely of these patients presenting with advanced diseas (Stagee IIIB or Stage IV) at the time of diagnosis About. 30% of NSCLC tumors contain activat KRASing mutations and, these mutations are associated with resistance to EGFR tyrosine kinase inhibitor (TKIs s). Activat ingKRAS mutations are also frequently found in melanoma, 30WO 2021/171260 PCT/IB2021/051641 pancreatic cance andr ovarian cancer. BRAF mutations have been observe ind up to 3 % of NSCLC and have also been describe asd a resista ncemechanism in EGFR mutation positive NSCLC. id="p-116" id="p-116" id="p-116" id="p-116" id="p-116"
[00116] CRC is a common diseas withe more than 1.8 million new case estimas ted worldwi inde 2018, along with >800,000 deaths (World Health Organizatio Globocan, 2018)n .
Mutations in genes encoding components of the MAPK pathwa arey common, with RAS mutations occurring in approximately 50% of CRC. Activati mutationng in sthe gene encoding BRAFV600E are prese ntin approximat 10-15%ely of CRC patients, and mutated BRAFconfer a s poor prognosis. The V600E mutation occurs in approximately 90% of STMF-mutant CRC, though others for, example V600D, or V600K mutation ares also seen. id="p-117" id="p-117" id="p-117" id="p-117" id="p-117"
[00117] Effective treatme optionsnt for A7?d/■-mutant CRC are limite d.Unlike melanoma, where single-agent BRAF inhibitors yielded response ratess of approximately 70% in the metastatic settin singleg, agent inhibition of metasta A7?ticd /■-mutant CRC with vemurafeni wasb associated with an ORR of approximately 5%. Combination therapy with agents target theing MAPK pathway have improve upond the effectivenes of BRAFs inhibition, though outcomes are still poor. Dabrafenib combined with the MEK inhibitor trametinib was associated with an ORR of 12% and progression-free surviva (PFlS) of 3.5 months. id="p-118" id="p-118" id="p-118" id="p-118" id="p-118"
[00118] In CRC, stimulation of RAS through growth factor-mediate receptd tyrosineor kinase activat supporion tsthe oncoge nicmilieu. Inhibitors of EGFR modest improvedly upon the effectiveness of BRAF inhibition; BRAF inhibitors combine withd EGFR inhibitor weres associated with ORRs of 4-22% and PFS 3.2-4.2 months. Patients treated with dabrafeni + b trametinib + panitumumab experienced an ORR of 21% and PFS of 4.2 months In. the phase III BEACON trial patient, weres randomize to done of three arms in the 2nd-line of treatme ornt higher: encorafenib/binimetinib/cetuxima encorab,fenib/cetuximab, versus irinotecan/cetuximab or FOLFIRI/cetuximab (control). Patients receiving triplet therapy achieved an ORR of 26%, PFS of 4.3 months and, overa survill val (OS) of 9 months. Encorafe plusnib cetuxima wasb associated with an ORR of 20% and PFS of 4.2 months, and OS of 8.4 months. Both regimens achieve statisticd signifally icant improveme ntsover irinoteca or nFOLFIRI/cetuxima whichb, was associated with an ORR of 2%, a PFS of 1.5 months, and OS of 5.4 months The. improv ed outcomes demonstrate by combid ned inhibition of RAF, MEK, and EGFR signal ingsupport the 31WO 2021/171260 PCT/IB2021/051641 concept that inhibition of multiple nodes within the MAPK pathwa is yrequire ford the treatment ofBRAF V600E CRC. id="p-119" id="p-119" id="p-119" id="p-119" id="p-119"
[00119] Dabrafenib (Tafinlar® is an) orall bioavailaby potentle, and selecti inhibitorve of RAF kinase whoses, mechanism of action of is consistent with competitive inhibition of adenosin triphoe spha (ATP)te binding The. ability of dabrafenib to inhibit some mutated forms of BRAF kinase iss concentrati dependeon nt,with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes respec, tively. Inhibition of wild-type BRAF and CRAF kinase requis res higher concentrations, with IC50 values of 3.2 and 5.0 nM, respectively. Othe kinaser suchs as SIK1, NEK11, and LIMK1 may also be inhibite atd higher concentrat Dabrafions. enib inhibits cel growtl ofh various BRAF V600 mutation-pos itivetumor s in vitro and in vivo. id="p-120" id="p-120" id="p-120" id="p-120" id="p-120"
[00120] Dabrafenib was first approved by the FDA in 2013 as a single-agent oral treatment for unresecta orble metastatic melanoma in adult patient withs the BRAF V600 mutation and is approved in various other countries for the same indication. Dabrafenib in combination with trametinib is also approved in multiple countries for the following indicati ons(approve d indications vary by countr y):treatment of patient withs unresectable or metastatic melanoma with a BRAFV600 mutatio then; adjuva nttreatment of patient withs Stage III melanoma with a BRAFV600 mutation, following complete resecti on;treatment of patients with advance non-d sma llcell lung cancer (NSCLC) with a BRAFV600 mutation; and treatment of patients with locally advance ord metasta anapltic ast thyroidic cancer (ATC) with a BRAFV600E mutation. id="p-121" id="p-121" id="p-121" id="p-121" id="p-121"
[00121] The recommen deddose of dabrafeni is b150 mg BID (corresponding to a total daily dose of 300 mg). id="p-122" id="p-122" id="p-122" id="p-122" id="p-122"
[00122] Compoun Ad is a potent sel, ecti andve orall bioavaily able ATP-competit ive ERK1/2 kinase inhibitor that exhibits physical chemical properties enabli ngcombinations with RAF and MEK inhibitors or other, targe tedtherapeutic agents Compoun. Ad effectively inhibits pERK signaling and has demonstr atedtumor growth inhibition in multiple MAPK-activate d cancer cells and xenogr aftmodels. Importantly, compound A demonstr atedbroad efficacy target multipleing known mechanisms of resistanc to BRAFe and MEK inhibito rs,including RAS mutations BRAF, splice varia ntsand MEK1/2 mutations, as shown in engineered cell line model s.
Compoun Ad has been dose din patient betwes en 45 mg and 450 mg QD. 32WO 2021/171260 PCT/IB2021/051641 id="p-123" id="p-123" id="p-123" id="p-123" id="p-123"
[00123] Clinic alstudie ins BRAF V600E CRC have demonstrate that thed activity of BRAF inhibitors alone or in combination with MEK ± EGFR inhibitors is limited by insufficie nt MAPK pathwa suppry ession, and that in patients, mechanisms of resistanc quicklye arise even in the settin ofg initial clinical benefi t.Acquired resistance mechanisms leading to MAPK pathway reactivat inion patient tumor primaris involly veactivating genetic alterat inions RAS, BRAF or MEK. This highlights the relian ofce BRAF V600E CRC on MAPK signaling, and suggest thats inhibition of ERK, the most downstrea pointm of the signal ingpathway, may circumvent resistan occurce ring at upstream nodes. id="p-124" id="p-124" id="p-124" id="p-124" id="p-124"
[00124] Preclinica modelsl of RAS, RAF, or MEK resista ncemutation engines ere intod a BRAF V600E cell line supported this concept. While the parental BRAF V600E cel linel was sensiti veto combinations of BRAF, MEK, EGFR, and/or ERK inhibito rs,the introduction of KRAS, NRAS, MEK1, or MEK2 resistance mutations resulted in decreas sensed itivity of engineered BRAF V600E cells to all inhibito combinations,r except for those containi anng ERK inhibitor. Furthermore, the outgrowth of pre-existing, low-freque pooledncy resistant clone ins mouse xenografts was suppressed more effectively by treatment with drug combinations containi BRAFng and ERK inhibitors as ,compare tod BRAF and MEK inhibitors. id="p-125" id="p-125" id="p-125" id="p-125" id="p-125"
[00125] The combination of Dabrafenib + Compoun Ad was tested in vivo in the BRAF mutant human cell line xenograft HT29. Mice treated with Dabrafenib + Compound A achieve d similar anti-tumor response as compar toed Dabrafenib +Trametinib at clinically relevan dosest (36% T/C vs 28% T/C, respectivel Singley). agent treatment led to progressive diseas where, eby compound A achieved 54% T/C, Dabrafenib achieve 59%d T/C, and Trametinib achieved 48% T/C. All regime nswere tolerat as edjudged by lac ofk significant body weight loss These. data suggest that the combination of Dabrafenib + Compoun Ad may achie vesimilar anti-tum or activi toty Dabrafenib + Trameti nibin patient withs BRAF mutant colorectal cancer, and provide s rational for eits use in the clinic. id="p-126" id="p-126" id="p-126" id="p-126" id="p-126"
[00126] The improved outcomes demonstrate by combined inhibitd ion of BRAF, MEK, and EGFR signaling support the conce thatpt inhibition of multiple nodes within the MAPK pathway is require ford the treatment of BRAF V600 CRC. id="p-127" id="p-127" id="p-127" id="p-127" id="p-127"
[00127] Nonethele intrinsicss, and acquire resid sta nceto therapy rema inimportant challenges, and clinica outcl omes are still poor. There is a role for combination therapi thates provide more robust suppression of MAPK signal ingand addres thes complexity of mechanis ms 33WO 2021/171260 PCT/IB2021/051641 of resistance both within and beyond the MAPK pathway. Given the adaptive complexity of signa transl duction that character 77?dizes /■-mutant CRC, inhibition of proteins beyond RAF and ERK is required. As an illustra tion,one study of 218 BRAF-V600E mutated CRC tumors identifi disted inct subsets of tumors characteri byzed high KRAS/mTOR/AKT/4EBPl/EMT activatio whilen, cell-cycle dysregulati characon teriz the edother subset. id="p-128" id="p-128" id="p-128" id="p-128" id="p-128"
[00128] Despite the advances demonstrate by targed tedtherapy combinations such, as those studied in the BEACON trial (Kopetz et al. 2019), the ability to shut down the BRAF V600 oncogenic drive in cancer cell iss limited by 1.) the inability to fully suppres BRAFs activi duety the adaptive ability of RAF kinas esto signa throughl ineffectivel inhibitey dimerd s,and 2.) ongoing ERK activat stimulaion tednot only by adaptive mechanisms within the MAPK pathway, but also through parallel signal ingpathways Dabraf. enib, vemurafenib and, encorafenib effectively suppres BRAFs activity in A7?d/■-mutant cancer cells where monomeric V600E is an oncogenic drive r.Howeve theser, drugs may als olead to the paradoxica activatl ofion ERK through sever mechanial sms. id="p-129" id="p-129" id="p-129" id="p-129" id="p-129"
[00129] Combined inhibition of BRAF and MEK improves upon pathwa suppry ession; howeve ther, persistenc of ERKe signal ingunderlies the limitations of this therapeutic approac h.
Blockade of ERK, the ultimate signal of the MAPK pathway, may circumvent adaptive upstrea m signals and provide for improv edefficacy and resilience to acquired resistance. id="p-130" id="p-130" id="p-130" id="p-130" id="p-130"
[00130] BRAF-selective inhibitors are effective against constitutive actlyivate d monomeric BRAF V600; however, intrins andic acquir edresistanc to RAFe inhibito developrs at multiple level ofs the MAPK pathwa Undery. steady-sta conditite ons, activate MAPKd signali ng through BRAF V600E leads to ERK-dependent negative feedbac onk signa lsgenerat throued gh activated RAS. In BRAF V600 CRC, intrinsic resista nceto RAF inhibition manife stsbecause drugs such as dabrafeni effecb tively inhibit monomeric BRAF V600E signali throughng MEK to ERK; however this, in turn relea sesERK-depende negatnt ivefeedbac intok RAS signaling.
Therefore, upstream signals such, as through the epiderm growthal factor receptor (EGFR), are able to activate RAS. This in turn leads to the induction of BRAF V600E and wild-type homo- and heterodimer includings, homodimer ands heterodimers of WT and BRAF-V600E, CRAF and BRAF-V600E and ARAF and BRAF-V600E that signal to MEK. Moreover RAF, inhibitors such as dabrafeni allosteb rica promotelly the homo- and hetero- dimerization of RAF family members 34WO 2021/171260 PCT/IB2021/051641 such that inhibitor binds to only one RAF partn whileer the other unbound dimer partner is catalyticall activ yine stimulat downstreaing signalim ng. id="p-131" id="p-131" id="p-131" id="p-131" id="p-131"
[00131] Therefore, agents such as dabrafenib targ V600Eet monomer ins BRAF-dependent CRC cells leaving, RAS-stimulat dimered signal ingunopposed. This leads to ERK reactivat toion a great degreeer than is seen in BRAF V600E melanoma thus, limiting the effectiveness of therapy in CRC. In addition, CRAF plays an essential role in mediating paradoxica activatl ion following BRAF-inhibitor treatment Thus,. RAF inhibito rs,such as Compound C, that potentl y inhibit the activi ofty CRAF and BRAF can be effective in blocking STMF-mutant tumor and s RAS-drive adaptiven MAPK activation. The role of CRAF in resista nceto therapy underli thees rational for ethe inclusi onof an agent that inhibits both B- and CRAF in a triple combination. id="p-132" id="p-132" id="p-132" id="p-132" id="p-132"
[00132] The triple combination of dabrafeni + Compoundb A + Compound C can inhibit the MAPK pathwa iny BRAF V600E/K/D colorec cancertal by leveraging the potentia to l uniquely targ mechanet isms of intrinsic and acquired resistan ince BRAF V600-driven cancer cells. id="p-133" id="p-133" id="p-133" id="p-133" id="p-133"
[00133] Though single-agent checkpoint blockade is not effective in the treatment of microsatel stablelite CRC, the treatment of MSI-H CRC with anti-PD-1 antibodie hass been associated with response rates of 31-50%. Though approximately 21% of BRAF V600E CRC may exhibit MSI-H status, microsatell instaitebility does not appea tor modify responsive nessto MAPK-targeted therapy in this disease Theref. ore, subjects with MSI-H BRAF V600E CRC may respond to either RAF/MEK/ERK-target therapyed or checkpoint blockade. By address theing co-occurring feature ofs oncogenic BRAF and immunother respoapy nsive nessin MSI-H BRAF- mutant CRC, the combination of MAPK pathwa inhibitiony with checkpoint blocka hasde the potential to improve upon the outcomes achieved with eith ercategor of ytherapy alone. id="p-134" id="p-134" id="p-134" id="p-134" id="p-134"
[00134] Furthermore, targeted smal molecl ule inhibito mayrs modulate the immune microenvironment. For instance prec, linic studiesal demonstrate that MAPKd pathwa inhibitorsy could improve lymphocyte homing and function by increas ingtumor infiltrat lymphocytesing in tumors, decreas ingupregulate immunosd uppres sivecytokines, and general counterly actin g immune tolerance of cancer. Furthermore the BRAF-M, APK signal ingpathway is essential for cancer-immune evasion in human melanoma cells There. for RAFe, and MEK inhibitors can modulate the immune response to tumors and, the combination of such agents with checkpoint 35WO 2021/171260 PCT/IB2021/051641 blocka cande even increase the susceptibility of "immun ecold" tumors, such as microsatelli te stable CRC, to PD-1 inhibition. id="p-135" id="p-135" id="p-135" id="p-135" id="p-135"
[00135] The triple combination of dabrafenib + Compound A + Spartalizuma canb inhibit the MAPK pathwa iny BRAF V600E/K/D colorec cancertal by leveraging the potentia to l uniquely targ mechanet isms of intrinsic and acquired resistan ince BRAF V600-driven cancer cells.
Pharmaceutical Compositions id="p-136" id="p-136" id="p-136" id="p-136" id="p-136"
[00136] In another aspect, the present invention provide pharmaceuticas accllyeptab le compositions whic hcomprise a therapeutically-e amountffective of dabrafenib, compound A and compound C, formula togetherted with one or more pharmaceutic acceptaally carble rier s (additives) and/o diluer nts. As describe ind detail below, the pharmaceut compoical sitions of the present invention may be speciall formuy late for dadministration in solid or liquid form , including those adapte ford oral administrati foron, example, drenches (aqueous or non- aqueous solutions or suspensions table), ts,e.g., those targe tedfor buccal, sublingual, and systemic absorption, boluse s,powders, granules pastes, for applicat toion the tongue. id="p-137" id="p-137" id="p-137" id="p-137" id="p-137"
[00137] The phras "pharmae ceutically-acc carreptableier" as used herei meann as pharmaceutically-acceptable material, composition or vehicle such, as a liquid or solid filler, diluent, excipient, manufactur aiding (e.g., lubrica nt,talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsula tingmaterial, involved in carrying or transporti ng the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carri muster be "acceptable in the" sense of being compatible with the other ingredients of the formulati andon not injurious to the patient. Some examples of materi als which can serv ase pharmaceutically-acce carrptableiers include (1): sugars, such as lactose, glucose and sucrose; (2) starche suchs, as com starch and potato starch; (3) cellulose and, its derivati vessuch, as sodium carboxymethyl cellulose ethyl, cellulose and cellulos acetae te;(4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppositor waxes;y (9) oils, such as peanut oil, cottonse oil,ed safflowe oil, rsesame oil, olive oil, com oil and soybean oil; (10) glycols such, as propylene glycol (11); polyols such, as glyceri sorbin, tol, mannitol and polyethylene glycol; (12) esters such, as ethyl oleate and ethyl 36WO 2021/171260 PCT/IB2021/051641 laurate (13); agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide (15); algin acidic (16); pyrogen-fr wateee (17)r; isotonic saline; (18) Ringer's solutio (19)n; ethyl alcohol; (20) pH buffered solutions; (21) polyest ers,polycarbonates and/or polyanhydrides and (22); other non-toxic compatible substances employed in pharmaceutic formal ulations. id="p-138" id="p-138" id="p-138" id="p-138" id="p-138"
[00138] As set out above, certain embodiments of the prese ntcompounds may contain a basi cfunctiona group,l such as amino or alkylamino, and are, thus cap, able of forming pharmaceutically-acceptable salts wit hpharmaceutically-acceptable acids The. term "pharmaceutically-ac saltsceptable in" this respect, refers to the relative non-toxicly inorganic, and organic acid addition sal tsof compounds of the prese ntinvention. Thes esalt cans be prepared in situ in the administrat vehiioncle or the dosage form manufactur procing ess or, by separately reacti ang purifie compod und of the invention in its fre ebase form with a suitable organi orc inorga nicacid and, isolatin theg salt thus forme duringd subseque ntpurification .
Representati saltve includes the hydrobromi hydrochloride,de, sulfa te,bisulfate, phosphat e, nitrate acet, ate valera, oleatete, palmit, ate ste,ara laurte, ate benzoa, te, lactate phosphat, e, tosyla citrate, te,maleat fumae, rate suc, cinate tart, rate, napthyl ate,mesylate glucohe, ptonate , lactobionate and laury, lsulphonate salts and the like. id="p-139" id="p-139" id="p-139" id="p-139" id="p-139"
[00139] The pharmaceutic acceptaally saltble ofs the subject compounds include the conventional nontoxic salt ors quatern ammoniuary msalt ofs the compounds, e.g., from non- toxic organic or inorga nicacids For. example, such conventional nontoxic sal tsinclude those derived from inorga nicacids such as hydrochlori hydrode, brom sulfic, uric, sulfamic , phosphor nitricic, and, the like and; the salt prepas red from organic acid suchs as acet ic, propionic succ, inic glycolic,, stear lacic, tic malic, tart, aric, citric ascorbic,, palmitic male, ic, hydroxyma leiphenylacetic,c, glutamic, benzoic, salicyclic, sulfanilic 2-ac, etoxybenz oic, fumaric, toluenesulf onic,methane sulfonic etha, nedisulfoni oxalicc, isot, hionic and, the like. id="p-140" id="p-140" id="p-140" id="p-140" id="p-140"
[00140] In othe casesr the, compounds of the prese ntinvention may contain one or more acidic functional group and,s thus, are capable of forming pharmaceutically-acc eptable salts wit hpharmaceutically-ac basesceptab .Thele term "pharmaceutically-a ccesaltptable s" in these instanc refes ers to the relative non-toxicly inorga, nicand organi basec addition salts of compounds of the prese ntinvention. Thes esal tscan likewise be prepared in situ in the administration vehicle or the dosage form manufactur processing or, by separate reactingly 37WO 2021/171260 PCT/IB2021/051641 the purified compound in its free acid form wit ha suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acc metaleptable cation, wit hammonia, or with a pharmaceutically-acc orgaeptanic primable ry, secondar or tery tiar amine.y Representati alkalive or alkaline earth sal tsinclude the lithium, sodium potassi, um, calcium, magnesium, and aluminum salt ands the like. Representati organicve amine uses ful for the formati ofon base addition sal tsinclude ethylamine, diethylam ethyleneine, diamine , ethanolamine, diethanolami piperazne, ine and the like. id="p-141" id="p-141" id="p-141" id="p-141" id="p-141"
[00141] A particularly preferr salted of dabrafenib is the mesylat salte thereof. A particularly prefer redsolva ofte compound A is the hydrochlorid salt thereofe A .particularly preferr formed of compound C is the free base crystalli form.ne id="p-142" id="p-142" id="p-142" id="p-142" id="p-142"
[00142] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfa teand magnesium stearate, as well as color ingagents, release agents, coating agents, sweetening, flavor anding perfuming agents, preservatives and antioxida cannts als beo present in the compositions. id="p-143" id="p-143" id="p-143" id="p-143" id="p-143"
[00143] Examples of pharmaceutically-ac anticeptaboxidale includents (1): water soluble antioxidants, such as ascorbic acid cyste, ine hydrochlori sodiumde, bisulfate, sodium metabisulfite sodium, sulfite and the like (2); oil-soluble antioxida nts,such as ascorbyl palmitate butylated, hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate alph, a-tocopher and ol,the like and; (3) metal chelating agents, such as citric acid, ethylenediami tetrneaace acidtic (EDTA), sorbitol, tartar acidic phosphoric, acid and, the like. id="p-144" id="p-144" id="p-144" id="p-144" id="p-144"
[00144] Formulations of the prese ntinvention include those suitable for oral, nasal , topical (including buccal and sublingual), rectal, vaginal and/o parenter adminral istration.
The formulations may conveniently be presented in unit dosage form and may be prepared by any methods wel knownl in the art of pharmacy. The amount of active ingredient which can be combined with a carri mateer ria to producl ae single dosage form will vary dependi ngupon the host being treated, the particula moder of administration. The amount of active ingredie nt which can be combined wit ha carri materialer to produc ae single dosage form will generall y be that amount of the compound which produce a stherapeuti effcec t.General outly, of one hundred per cent this, amount will range from about 0.1 per cent to about ninety-n inepercent of active ingredient, preferab fromly about 5 per cent to about 70 per cent most, preferabl y from about 10 percent to about 30 percent. 38WO 2021/171260 PCT/IB2021/051641 id="p-145" id="p-145" id="p-145" id="p-145" id="p-145"
[00145] In certa embodimein nts, a formulati ofon the prese ntinvention compris anes excipient selected from the group consist ingof cyclodextri celns,lulo sesliposomes,, micelle forming agents, e.g., bile acids and, polymeric carrie e.g.,rs, polyeste andrs polyanhydride s; and a compound of the prese ntinvention. In certai embodimen nts, an aforementi oned formulati rendeon orallrs bioavay ilabl a compoue nd of the prese ntinvention. id="p-146" id="p-146" id="p-146" id="p-146" id="p-146"
[00146] Methods of preparing these formulations or compositions include the step of bringing into associatio a compoun nd of the present invention wit hthe carri and,er optionally, one or more accessory ingredient Ins. gener al,the formulations are prepared by uniform ly and intimatel bringy ing into associatio a compon und of the prese ntinvention wit hliquid carrier ors, finel dividey solid dcarrie orrs, both, and then, if necessa ry,shaping the product. id="p-147" id="p-147" id="p-147" id="p-147" id="p-147"
[00147] Formulations of the invention suitable for oral administrat mayion be in the form of capsules cac, hets pills,, table ts,lozenges (using a flavored basis, usuall sucry ose and acacia or tragacant powdeh), rs, granules or as, a solution, suspension or soli dispersd ion in an aqueous or non-aqueous liquid, or as an oil-in-wate or water-r in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glyceri orn, sucrose and acacia) and/o asr mouth washes and the like, each containi ang predetermine amountd of a compound of the prese ntinvention as an active ingredient A compou. nd of the prese nt invention may also be administer ased a bolus, electuary or paste. id="p-148" id="p-148" id="p-148" id="p-148" id="p-148"
[00148] In solid dosage forms of the invention for oral administration (capsules, table ts,pills dragees,, powders, granules, trouches and the like) the, active ingredie isnt mixed with one or more pharmaceutically-ac carrierceptab suchles, as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fille orrs extenders such, as starches lactose,, sucros glucose,e, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcel alginalulose, tes,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia (3); humectants, such as glycerol (4) disi; ntegrat ageingnts, such as agar-aga calcr, ium carbonate, potato or tapioc staa rch, algin acidic cer, tai silican tes, and sodium carbonat (5)e; solution retarding agents, such as paraffin; (6) absorpt ionaccelerators such as, quaterna ammory nium compounds and surfactants such ,as poloxamer and sodium lauryl sulfat (7)e; wetti ngagents, such as, for example, cetyl alcohol glycer, monostol ear andate non-ionic, surfactants; (8) absorbents such, as kaolin and bentonite clay; (9) lubricant suchs, as talc, calcium stearate , magnesium steara solidte, polyethyle glycolsne sodium, lauryl sulfa te,zinc steara sodiumte, 39WO 2021/171260 PCT/IB2021/051641 stearate stearic, acid and, mixtures thereof (10); color ingagents; and (11) controlled release agents such as crospovidone or ethyl cellulose In the. cas eof capsule tabletss, and pills the, pharmaceutic compoal sitions may als ocomprise bufferi ngagents. Solid compositions of a simila typer may also be employed as fdlers in soft and hard-shelled gelatin capsules using such excipients as lactos ore milk sugars, as wel asl high molecular weight polyethyle ne glycols and the like. id="p-149" id="p-149" id="p-149" id="p-149" id="p-149"
[00149] A tablet may be made by compress ionor molding, optionally wit hone or more accessory ingredient Comprs. ess tableed mayts be prepared using binde (forr example, gelatin or hydroxypropylmethyl cellulose lubric), ant, inert diluent, preservative, disintegra nt (for example, sodium star chglycolate or cross-linked sodium carboxymethyl cellulos e), surface-acti or vedispersin agent.g Molded tablets may be made by molding in a suitable machine a mixtur ofe the powdered compound moistened with an inert liquid diluent. id="p-150" id="p-150" id="p-150" id="p-150" id="p-150"
[00150] The table ts,and othe solir dosad ge forms of the pharmaceut compositiical ons of the present invention, such as dragee capss, ules pills, and granules may, optionally be score ord prepared with coatings and shell suchs, as enteric coatings and othe coatingsr well known in the pharmaceutical-for mulatingart. They may also be formulated so as to provide slow or controll releedase of the active ingredient therein using, for exampl e, hydroxypropylmet cellulosehyl in varying proporti onsto provide the desire reled ase profile , othe polymerr matrices, liposomes and/or microspheres They. may be formula forted rapi d release e.g.,, freeze-drie Theyd. may be sterilize by,d for example, filtra tionthroug a h bacteria-retai filter,ning or by incorporati sterilng izing agents in the form of steril solide compositions which can be dissolved in steril watee orr, some othe sterr ileinjecta blemedium immediately befor use.e These compositions may also optional containly opacifying agents and may be of a composition that they release the active ingredient( only,s) or preferentia lly, in a certain portion of the gastrointes tractinal optionalt, inly, a delaye manned r.Example ofs embedding compositions which can be used include polymeric substances and waxes. The active ingredient can als beo in micro-encapsula form,ted if appropriat withe, one or more of the above-described excipients. id="p-151" id="p-151" id="p-151" id="p-151" id="p-151"
[00151] Liquid dosage forms for oral administrat ofion the compounds of the invention include pharmaceutic accallyepta emulsions,ble microemulsi ons,solutions, suspensions, syrups and elixirs. In additi onto the active ingredient, the liquid dosage forms may contain 40WO 2021/171260 PCT/IB2021/051641 inert diluents commonly used in the art, such as, for example, water or othe solvenr ts, solubilizing agents and emulsifie rs,such as ethyl alcohol, isopropyl alcohol ethyl, carbona te, ethyl acetat benze, yl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular cotto, nsee groundnutd, com,, germ, olive, cast orand sesame oils), glycerol, tetrahydrofuryl alcohol polyethyle, glycne ols and fat tyacid esters of sorbita andn, mixtures thereof. id="p-152" id="p-152" id="p-152" id="p-152" id="p-152"
[00152] Besides inert diluents, the oral compositions can als oinclude adjuvant suchs as wetti ngagents, emulsifying and suspendin ageg nts, sweetening, flavori coloring,ng, perfuming and preservative agents. id="p-153" id="p-153" id="p-153" id="p-153" id="p-153"
[00153] Suspensions, in addition to the active compounds may, contai susn pendin g agents as, for example, ethoxylat isosedtear alcylohols polyoxyethylene, sorbitol and sorbitan esters micr, ocryst allicellulose,ne aluminum metahydroxide benton, ite, agar-aga andr tragaca andnth, mixture thers eof. id="p-154" id="p-154" id="p-154" id="p-154" id="p-154"
[00154] Examples of suitable aqueous and nonaqueous carriers which may be employe ind the pharmaceutic compoal sitions of the invention include water, ethanol polyols, (such as glycero propylenel, glycol, polyethyle glycol,ne and the like), and suitable mixture s there of,vegetable oils, such as olive oil, and injecta bleorganic esters such, as ethyl olea te.
Proper fluidity can be maintaine ford, example, by the use of coating material suchs, as lecith byin, the maintenance of the require particld sizee in the cas eof dispersions, and by the use of surfactants. id="p-155" id="p-155" id="p-155" id="p-155" id="p-155"
[00155] These compositions may als ocontai adjun vant suchs as preservative wettis, ng agents, emulsifying agents and dispersing agents. Prevention of the action of microorganism s upon the subject compounds may be ensured by the inclusion of various antibacterial and antifunga agelnts, for example, parabe chlorn, obutanol phenol, sorbic acid and, the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. id="p-156" id="p-156" id="p-156" id="p-156" id="p-156"
[00156] When the compounds of the prese ntinvention are administered as pharmaceutica to humansls, and animals, they can be given per se or as a pharmaceut ical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combinat ionwit ha pharmaceutic acceptaally carble rier. 41WO 2021/171260 PCT/IB2021/051641 id="p-157" id="p-157" id="p-157" id="p-157" id="p-157"
[00157] The compounds of the prese ntinvention and/or the pharmaceutical compositions of the present invention, are formulate intod pharmaceutically-ac ceptable dosage forms by conventional methods known to those of skill in the art. id="p-158" id="p-158" id="p-158" id="p-158" id="p-158"
[00158] Actua dosal ge levels of the active ingredients in the pharmaceutic al compositions of this invention may be varie sod as to obtain an amount of the active ingredient which is effective to achie vethe desired therapeuti rescpons fore a particular patient, composition, and mode of administrat withoution, being toxic to the patient. id="p-159" id="p-159" id="p-159" id="p-159" id="p-159"
[00159] The selected dosage leve willl depend upon a varie tyof factors including the activit ofy the particular compound of the prese ntinvention employed, or the ester salt, or amide there of,the route of administrat theion, time of administrati theon, rate of excreti onor metabolis ofm the particular compound being employed, the rate and extent of absorption the , duration of the treatment, othe drugsr compounds, and/or materi alsused in combinat ionwit h the particula compor und employe thed, age, sex, weight, condition, general healt andh prior medica historyl of the patient being treated, and like factors wel knownl in the medical arts. id="p-160" id="p-160" id="p-160" id="p-160" id="p-160"
[00160] A physician or veterinar havingian ordinar skilly in the art can readi ly determine and prescr ibethe effecti amountve of the pharmaceut composiical tion require d.
For example, the physici anor veterinarian coul dsta rtdoses of the compounds of the invention employe ind the pharmaceutic composial tion at levels lower than that require ind order to achieve the desired therapeuti effcect and gradually increase the dosage until the desire effd ect is achieved. id="p-161" id="p-161" id="p-161" id="p-161" id="p-161"
[00161] In general, a suitable daily dose of the combination of the invention will be that amount of each compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. id="p-162" id="p-162" id="p-162" id="p-162" id="p-162"
[00162] In another aspect, the present invention provide pharmaceuticas accllyeptab le compositions whic hcomprise a therapeutically-e amountffective of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutic ally accepta carrble iers (additiv esand/or) diluents. 42WO 2021/171260 PCT/IB2021/051641 Examples Example 1 Dabrafenib. Compound A and Compound C id="p-163" id="p-163" id="p-163" id="p-163" id="p-163"
[00163] Dabrafenib is synthesized according to example 58a of WO2009/137391.
Compound A is synthesized according to example 184 of WO2015/066188. Compound C is synthesized according to exampl 1156e of WO2014/151616. WO2009/137391, WO2015/066188 and WO2014/151616, are herei incorporan byted reference in thei entir rety .
The utility of a combinat ionof Dabrafenib, Compound A and Compound C described here in can be evidenced by testing in the followi exangmples.
Example 2 Combination efficacy of MAPK pathwa inhibitorsy in the human BRAF mutant CRC xenogr aft model HT29 in nude mice id="p-164" id="p-164" id="p-164" id="p-164" id="p-164"
[00164] Dabrafenib (DRB436): selecti inhibitorve of mutated BRAF at V600 capable of inhibiting BRAF(V600E), BRAF(V600K) and BRAF(V600G) mutations Compound. A: selecti ATP-competive tive ERK1 and ERK2 kinase inhibitor. Compound C: an ATP competitive inhibito ofr BRAF and CRAF. Dabrafenib was dose p.o.d in vehicle: 0.5% HPMC + 0.2% Twee n 80 in pH 8 DI wate r.Compound A was dosed p.o. in vehicle: 0.5% HPC / 0.5% Pluronic F127 in a pH 7.4 phospha buffer,te adjusted to pH 4.0 with acid. Compound C (fre basee crystalline form, in powder form) was dose dp.o. in MEPC4 vehicl (45%e Cremophor RH40 + 27% PEG400 + 18% Capmul MCM C8 + 10% ethanol). id="p-165" id="p-165" id="p-165" id="p-165" id="p-165"
[00165] The HT29 human colorectal cancer (CRC) tumor cel linel was purchas fromed ATCC and was include ind the Novart Cellis Line Encyclope (CLE)dia cell line collection. The line has been shown to be fre eof Mycoplasma sp. and murine viruses in the IMPACT-VIII PCR assay panel (Researc Animalh Diagnostic Laborat ory(RADIL), Univers ityof Missouri , Columbia MO)., The cells were maintaine in dEMEM (Lonza #12-61 IF) plus 10% FBS (Gibco #26140-079) (56°C for 30 min. inactivated), at 37°C in a humidified atmospher conte aini 5%ng carbon dioxide. Cell weres harves tedat 80-95% confluenc withe 0.25% trypsin-EDTA (Gibco #25200-056), neutralized with growth medium, afte centrifr ugatio for 5 nmin at 1200 rpm, 43WO 2021/171260 PCT/IB2021/051641 followe byd resuspension of the cell pellet in cold HBSS (Gibco #14175-095) and then mixed with an equal volume of Matrigel™ Matri (Comingx #354234) to prepare a final concentrat of ion 10xl06cells/mL. Then 200pl (2 x 106 cell wass) implanted subcutaneously into the right flank of fema lenude mice .Tumor volume was determined by measurem entwith calipers and calculat ed using a formula where, tumor volume (TV) (mm3) = (1 x w2)/2, where 1 is the longes axist of the tumor and w is perpendicul to ar1. Mice were monitored for tumor growt andh body weight twice/week. Animal well-being and behavior, including groomi ngand ambulation, were monitored twic weee kly. General health of mice was monitored daily. id="p-166" id="p-166" id="p-166" id="p-166" id="p-166"
[00166] The HCOX1329 CRC patient-deri tumorved xenogr aft(PDX) was propagated by seri alpassage of tumor slurr iny nude mice. Briefly, fragments of fresh tumor from a previous passage were homogenized using gentleMACS Dissociat (MACor S (Miltenyi Biote c,#120-005- 331), passe throughd a tissue grinder (Chemgla lifess Science # CLS-5020-085)s , and diluted in PBS. Then 4xlOA6 cells in lOOpl of tumor slur rywas implanted subcutaneously into the right flank of female nude mice as passage 7. Tumor volume was determined by measurem entwith caliper ands calculated using a formula, where tumor volume (TV) (mm3) = (1 x w2)/2, where 1 is the longes axist of the tumor and w is perpendicul to ar1. Mice were monitored for tumor growth and body weight twice/wee Animalk. well-bei ngand behavior, including grooming and ambulation, were monitored twice weekly. General health of mice was monitored daily. id="p-167" id="p-167" id="p-167" id="p-167" id="p-167"
[00167] The efficacy study design for each model is described in Table 1, Table 2 and table 3. Test agents were dose dat dose volume of 10 mL/kg, which was adjusted according to body weight. Tumor dimensions and body weights were collected at the tim eof randomization and twice weekly therea fterfor the study duration.
Table 1 Number Group Compound Dose (mg/kg) Route Schedule of mice 1 9 Vehicle - p.o. - 2 9 Dabrafenib 30 p.o. qd 3 9 0.3 Trametinib p.o. qd 4 9 Compound A 75 p.o. qd 9 Dabrafenib+trametinib 30+0.3 p.o+p.o. qd+qd 6 9 30+75 Dabrafenib+Compou A nd p.o+p.o. qd+qd 7 9 Dabrafenib+trametinib+Compound A 30+0.3+75 p.o.+p.o.+p.o qd+qd+qd 44WO 2021/171260 PCT/IB2021/051641 Table 2 Number Group Compound Dose (mg/kg) Route Schedule of mice 1 7 - - Vehicle p.o. 2 7 Dabrafenib+trametinib+Com A pound30+0.15+75 p.o.+p.o.+p.o qd+qd+qd 3 7 Dabrafeni Compoundb+ A+Compound C 30+75+25 p.o.+p.o.+p.o qd+qd+bid Table 3 Number of Group Compound Dose (mg/kg) Route Schedule mice 1 5 Vehicle - p.o. - 2 5 30+0.3 Dabrafenib+trametinib p.o.+p.o. qd+qd 3 5 Dabrafenib+tramet inib+ 30+0.3+20 p.o. +p.o.+i.p. qd+qd+biw cetuximab 4 5 Dabrafenib+tramet inib+ 30+0.15+75 p.o.+p.o.+p.o qd+qd+qd Compound A p.o.: per os (oral gavage) i.p.:; intraperitonea qd: oncel; a day; bid: twice a day; biw: twic ae week.
The percent change in body weight was calculated as (BWcuren -t BWinitia1)/(BWinitia1) x 100%. Data was presented as mean perce ntbody weight change from the day of treatment initiat ion± SEM.
Tumor volume: Perce nttreatment/c ontrol(%T/C) values were calculated using the followi ng formula %T/C: = 100 x AT/AC if AT > 0 ; % Regression = 100 x AT/Tmitiai if AT < 0; where: T = mean tumor volume of the drug-treated group on the final day of the study; AT = mean tumor volume of the drug-treat grouped on the final day of the study - mean tumor volume of the drug-treated group on initi alday of dosing; Tinitia =i mean tumor volume of the drug-trea groupted on initial day of dosing; C = mean tumor volume of the control group on the final day of the study; and AC = mean tumor volume of the control group on the final day of the study - mean tumor volume of the control group on initial day of dosing.
All data were expressed as mean ± standar errd or of the mean (SEM). Percen changet in tumor volume and body weight were used for statistical analysis Betwee. groupn comparisons were carried out using a one-way ANOVA followe byd a Tukey’s multiple comparisons test .For all statistica evall uations the leve ofl significan wasce set at p < 0.05. 45WO 2021/171260 PCT/IB2021/051641 id="p-168" id="p-168" id="p-168" id="p-168" id="p-168"
[00168] The antitumor efficacy of MAPK pathwa inhiy bitors was examined in two studies using the BRAF mutant HT29 human CRC xenograft model in athymic nude mice. In the first study (table 1), mice were treated with single agents or combinations of MAPK pathway inhibito asrs described on Table 1 until vehicle-trea tumorsted achieved a volume >1000 mm3, 13 days post treatment initiation. Anti-tumor activity was determined by assessing %T/C or % regression on day 39 post implant (13 days post treatment initiation). Anti-tumor activity mean, change in tumor volume, mean change in body weight and survival 13 days post treatment initiation is reporte in dTable 3. Tumor volume and body weight change post treatment are plotte ond Figure 1. Daily single agen treatt ment with Compound A, dabrafenib or trametinib achieve 54%T/C,d 59%T/C, or 48%T/C, respectively, when compare tod the vehicl treae ted group. The combined anti-tum actor ivity of Compound A+dabrafenib (35% T/C) was similar to the anti-tumor activity achieved by the trametinib+dabr afenibcombination (28%T/C), and the anti-tumor activity of both combinations was significantly different when compare tod dabrafeni b treatment (p=0.0037 for dabrafenib+trame vs tinibdabrafenib; p=0.03 for dabrafenib+Compound A vs dabrafenib but), not when compar toed tramet inibor Compound A treatments. In compariso then, tripl combinatie ofon Compound A+dabrafenib+tramet achiinibeved significant (p<0.05) anti-tum activior (3%T/ty C) when compared to the vehicle, all single agents and, each double combination groups (Tabl e1 and Figure 1). All treatment groups were well tolerat withed minima bodyl weight loss (les sthan 10%) at the end of the two week study; no signs of toxicity or mortali werety observe (Figured 1). id="p-169" id="p-169" id="p-169" id="p-169" id="p-169"
[00169] In the second study, the activity of the tripl combinatione of dabrafeni + b trametinib + Compound A was compare tod the triple combination of dabrafeni + Compoundb A + Compoun C.d Mice were treated with doses and regime nsdescribed in Table 2 until vehicl e- treated tumor achies ved a volume >1000 mm3, 24 days post treatment initiation. Anti-tumor activity was determined by assessing %T/C or % regression on day 52 post implant (24 days post treatment initiation). Anti-tumor activity mean, change in tumor volume, mean change in body weight and survival 24 days pos ttreatment initiat ionis reporte in dTable 4.
Table 4 Study Dose Days change in %ehange in Treatment 11،i! tumor volume body weight Su n ival days Model implant Mean+ZSEM 46WO 2021/171260 PCT/IB2021/051641 (mm3) Mcm1+/SEM 1073.95 ± Vehicle 39 13 -3.21 ± 1.38 9/9 146.00 39 13 577.31 ±75.78 9/9 Compoun Ad 75 qd -5.61 ± 1.58 trametinib 0.3 qd 39 13 511.85 ±68.46 -3.92 ±0.87 9/9 dabrafenib 30 qd 39 13 631.76 ± 39.70 -4.88 ± 1.25 9/9 7724/ Compoun Ad 75 qd+ 39 13 371.61 ±44.29 -5.95 ±0.91 9/9 HT29 +dabrafenib 30 qd trametinib 0.3 qd+ 39 13 302.45 ± 39.97 9/9 -7.34 ± 1.26 +dabrafenib 30 qd Compoun Ad + 75qd+ 0.3 qd+ 39 13 29.47 ± 17.55 9/9 trametini b+ -3.98 ± 1.23 dabrafenib 30 qd 1157.33 ± Untreate controld 52 24 5.57 ±2.91 4/7* 205.79 Compoun Ad + 75qd+ 166.09 ± 33.35 8031/ trametini b+ 0.15 qd+ 52 24 0.45 ± 0.93 7/7 HT29 dabrafenib 30 qd Compound C + 25 bid+ 56.52 ± 17.67 Compoun Ad + 75qd+ 52 24 -1.09 4 0.87 7/7 dabrafenib 30 qd 1685.22 ± 7.65 ± 1.10 Vehicle 38 26 238.87 5/5 0.3 qd+ 288.00 ± 55.77 1.74 ±0.90 trametini b+ 38 26 5/5 8243/ dabrafenib 30 qd HCOX 0.3 qd+ 222.98 ± 96.84 trametini b+ 2.83 ± 1.07 1329 dabrafenib + 30 qd+ 38 26 5/5 cetuximab 20biw 0.15 qd+ trametini b+ -153.71 ±20.61 5.58 ±2.46 38 26 4/4 dabrafenib + 30 qd+ Compoun Ad 75 qd *2 mice were sacrificed on day 49 and 1 mous ewas sacrificed on day 45 due to tumor volume 500mm>l 3 47WO 2021/171260 PCT/IB2021/051641 id="p-170" id="p-170" id="p-170" id="p-170" id="p-170"
[00170] Tumor volume and body weight change post treatment are plotted on Figure 2.
The combine anti-td umor activity of Compound A+trametinib+dabrafe (14%nib T/C) was similar and not-significantl diffeyrent (p=0.38) when compare tod the anti-tumor activity achieved by Compoun A+Compoud nd C+dabrafe nib(5%T/C). The anti-tum activityor of both combinations was significantly improved when compare tod the untreated control group (p<0.0001 for both groups against untreated control group) (Table 4 and Figure 2). All treatment groups were wel l tolerat withed minima bodyl weight loss (less than 10%) at the end of the study; no signs of toxicit ory mortal wereity observed (Figure 2). id="p-171" id="p-171" id="p-171" id="p-171" id="p-171"
[00171] Next, the antitumor efficacy of MAPK pathwa inhiy bitors was examined in the BRAF mutant patient-derived CRC xenogr aftmodel HCOX1329 in athymi nudec mice. Mice were treated with vehic leor combinations of MAPK pathway inhibitors as described in Table 3 until vehicle-tre tumorsated achieve a dvolume >1000 mm3, or 62-67 days post MAPK pathway inhibitor treatment initiation. Anti-tumor activity was determined by assessing %T/C or % regression on day 38 post implant (26 days post treatment initiation), at which point mice treate d with vehicl weree sacrifice andd mice treated with MAPK pathway inhibitors were treated for an additiona 24-29l days and were sacrifice ond day 62 (dabrafenib+Compound A+trametinib) or day 67 (dabrafenib+trametinib and dabrafenib+trametinib+tcet postuxima implant.b) Anti-tumor activi ty,mean change in tumor volume mean, change in body weight and surviva 26l days post treatment initiati ison reported in Table 4. Tumor volume and body weight change post 26-55 days of treatment are plotte ond Figur e3. The combined anti-tumor activity of dabrafenib+trametinib (17% T/C) was similar and not statistica signiflly icant (p=0.68) when compare tod the anti-tum activior achiety ved by trametinib+dabrafenib+c etuxima(13%T/C).b In compariso then, tripl combinatie ofon Compound A+dabrafenib+tramet achiinibeved tumor regression (70% Reg), which was significantly different compare tod both the dabrafenib+trametinib (p=0.005) or the dabrafenib+trametinib+tcetuximab combination (p=0.04) (Table 4 and Figure 3). All treatment groups were well tolerat withed minimal body weight loss (les sthan 10%) at the end of the two week study; no signs of toxicity or mortality were observ ed (Figure 3). id="p-172" id="p-172" id="p-172" id="p-172" id="p-172"
[00172] The in vivo activity of MAPK pathwa inhiy bito combinationsr was profile ind BRAF mutant CRC tumor xenograft Ins. the human BRAF mutant cell line derived xenograft 48WO 2021/171260 PCT/IB2021/051641 HT29, the combined activity of dabrafenib+tram wasetinib similar to that of dabrafenib + Compoun A,d and modest betterly when compar toed each single agent. In compariso then, trip le combinations of dabrafenib+Compound A+trameti ornib dabrafenib + Compound A + Compound C achieve signifd icant anti-tum actor ivity in this xenogr aftmodel In. the human patient derived BRAF mutant CRC xenogr aftHCOX1329, the combination of dabrafeni +Compoundb A+trameti wasnib also significantly more activ thane the combination of dabrafenib+trame tinib and dabrafenib+trametinib+tce Colletuximab.ctiv theseely, data indicate that the trip le combinations of dabrafenib+Compound A+trameti ornib dabrafenib+Compo A+Compoundund C can achieve greater and more durable responses in BRAF mutant CRC patients. id="p-173" id="p-173" id="p-173" id="p-173" id="p-173"
[00173] It is understo thatod the Example ands embodiments described herei aren for illustrati purposesve only and that various modifications or changes in light thereof will be suggeste tod persons skilled in the art and are to be include witd hin the spir itand purview of this applicat andion scope of the appended claims. 49

Claims (5)

PAT058765-WO-PCT Claims:
1. A pharmaceutical combination comprising: dabrafenib, or a pharmaceutically acceptable salt thereof, an Erk inhibitor (ERKi) which is 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4- hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2- fluorobenzamide (“Compound A” or “compound A”), or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor.
2. A pharmaceutical combination according to claim 1, wherein the PD-1 inhibitor is selected from PD-1 inhibitor is chosen from PDR001, Nivolumab, Pembrolizumab, Pidilizumab MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210 and AMP-224 .
3. A pharmaceutical combination according to claim 1 or 2, for use in treating cancer.
4. A pharmaceutical combination according to claim 1 or 2, for use in treating colorectal cancer.
5. A pharmaceutical combination according to claim 1 or 2, for use in treating BRAF gain of function colorectal cancer or for use in treating BRAF V600E, V600D or V600K colorectal cancer. 50
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