WO2022133731A1 - Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor and for the treatment of cancers - Google Patents
Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor and for the treatment of cancers Download PDFInfo
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- WO2022133731A1 WO2022133731A1 PCT/CN2020/138339 CN2020138339W WO2022133731A1 WO 2022133731 A1 WO2022133731 A1 WO 2022133731A1 CN 2020138339 W CN2020138339 W CN 2020138339W WO 2022133731 A1 WO2022133731 A1 WO 2022133731A1
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- compound
- methyl
- inhibitor
- cancer
- pharmaceutically acceptable
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Definitions
- the present invention relates to a KRAS G12C inhibitor and its uses in treating cancer (e.g. non-small cell lung cancer, colorectal cancer, pancreatic cancer or a solid tumor) alone and in combination with one or two additional therapeutically active agents.
- the present invention relates to a pharmaceutical combination comprising (i) a KRAS G12C inhibitor, such as Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a second therapeutic agent which is a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, or a PD-1 inhibitor.
- the present invention also relates to a triple combination comprising a KRAS G12C inhibitor, such as Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a second therapeutic agent which is a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor.
- a KRAS G12C inhibitor such as Compound A
- a second therapeutic agent which is a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor.
- the present invention also relates to pharmaceutical compositions comprising the same; and methods of using such combinations and compositions in the treatment or prevention of a cancer or a solid tumor.
- metastatic cancer remains largely incurable.
- the KRAS oncoprotein is a GTPase with an essential role as regulator of intracellular signaling pathways, such as the MAPK, PI3K and Ral pathways, which are involved in proliferation, cell survival and tumorigenesis.
- Oncogenic activation of KRAS occurs predominantly through missense mutations in codon 12.
- KRAS gain-of-function mutations are found in approximately 30%of all human cancers.
- KRAS G12C mutation is a specific sub-mutation, prevalent in approximately 13%of lung adenocarcinomas, 4% (3-5%) of colon adenocarcinomas and a smaller fraction of other cancer types,
- KRAS In normal cells, KRAS alternates between inactive GDP-bound and active GTP-bound states. Mutations of KRAS at codon 12, such as G12C, impair GTPase-activating protein (GAP) -stimulated GTP hydrolysis. In that case, the conversion of the GTP to the GDP form of KRAS G12C is therefore very slow. Consequently, KRAS G12C shifts to the active, GTP-bound state, thus driving oncogenic signaling.
- GAP GTPase-activating protein
- KRAS mutations are detected in approximately 25%of patients with lung adenocarcinomas (Sequist et al 2011) . They are most commonly seen at codon 12, with KRAS G12C mutations being most common (40%overall) in both adenocarcinoma and squamous NSCLC (Liu et al 2020) . The presence of KRAS mutations is prognostic of poor survival and has been associated with reduced responsiveness to EGFR TKI treatment.
- CRC Colorectal cancer
- Systemic therapy for metastatic CRC includes various agents used alone or in combination, including chemotherapies such as 5-Fluorouracil/leucovorin, capecitabine, oxaliplatin, and irinotecan; anti-angiogenic agents such as bevacizumab and ramucirumab; anti-EGFR agents including cetuximab and panitumumab for KRAS/NRAS wild-type cancers; and immunotherapies including nivolumab and pembrolizumab.
- chemotherapies such as 5-Fluorouracil/leucovorin, capecitabine, oxaliplatin, and irinotecan
- anti-angiogenic agents such as bevacizumab and ramucirumab
- anti-EGFR agents including cetuximab and panitumumab for KRAS/NRAS wild-type cancers
- immunotherapies including nivolumab and pembrolizumab.
- KRAS G12C is present in approximately 1-2%of malignant solid tumors, including approximately 1%of all pancreatic cancers (Biernacka et al 2016, Zehir et al 2017) .
- FIG. 1 Combinations of Compound A and TNO155 are synergistic in KRASG12C-mutated NSCLC cell lines.
- Figure 2 Compound A alone and in combination with TNO155 shows anti-tumor efficacy in a Lu99 KRASG12C lung carcinoma mouse xenograft models.
- Figure 3 A combination of Compound A with TNO155 is efficacious both when TNO155 is administered continuously (abbreviated as “cont. ” in Figure 3) and administered two weeks on and one week off.
- Figure 4 Efficacy of a combination of Compound A and TNO155 in CRC xenograft models.
- Compound A alone and in combination with another therapeutically active agent which is selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, a PD-1 inhibitor, and combinations thereofmay be useful in treating cancer, for example, cancers driven by KRASG12C mutations.
- a SHP2 inhibitor such as TNO155
- a pharmaceutically acceptable salt thereof such as TNO155
- a PD-1 inhibitor a pharmaceutically acceptable salt thereof
- a PD-1 inhibitor a pharmaceutically acceptable salt thereof
- Compound A may provide combination benefit in patients that have for instance acquired resistance to KRASG12C inhibitor by reactivation of RTK-MAPK pathway bypassing KRASG12C to signal through WT KRAS.
- Compound A may induce a pro-inflammatory microenvironment that enhances the efficacy of anti-PD-1 therapies such as spartalizumab. Combinations of Compound A with spartalizumab may thus result in improved anti-tumor activity compared to either single agent.
- Adding the SHP2 inhibitor TNO155 to Compound A plus spartalizumab may further decrease intracellular PD-1 signaling and lead to a less suppressive tumor microenvironment allowing for an improved immune response and better anti-tumor activity compared to single agent treatment or doublet combinations
- the present invention therefore provides a KRAS G12 C inhibitor which is 1- ⁇ 6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl ⁇ prop-2-en-1-one, (Compound A) , or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, as described herein.
- the present invention therefore also provides a pharmaceutical combination comprising a KRAS G12C inhibitor, such as Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a second therapeutically active agents selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor.
- a pharmaceutical combination comprising a KRAS G12C inhibitor, such as Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a second therapeutically active agents selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor.
- a triple combination consisting of Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor.
- the present invention also provides a pharmaceutical combination comprising
- the present invention provides a pharmaceutical combination comprising:
- the present invention provides a pharmaceutical combination comprising
- the present invention provides these pharmaceutical combinations for use in treating a cancer as described herein.
- the PD-1 inhibitor is chosen from PDR001 (spartalizumab; Novartis) , Nivolumab (Bristol-Myers Squibb) , Pembrolizumab (Merck & Co) , Pidilizumab (CureTech) , MEDI0680 (Medimmune) , REGN2810 (Regeneron) , TSR-042 (Tesaro) , PF-06801591 (Pfizer) , BGB-A317 (Beigene) , BGB-108 (Beigene) , INCSHR1210 (Incyte) , or AMP-224 (Amplimmune) .
- the PD-1 inhibitor is PDR001 (spartalizumab) .
- the PD-1 inhibitor e.g., spartalizumab
- the PD-1 inhibitor is administered at a dose of about 300-400 mg.
- the PD-1 inhibitor e.g., spartalizumab
- the PD-1 inhibitor is administered once every 3 weeks or once every 4 weeks.
- the PD-1 inhibitor e.g., spartalizumab
- the PD-1 inhibitor is administered at a dose of about 300 mg once every 3 weeks.
- the PD-1 inhibitor e.g., spartalizumab
- the PD-1 inhibitor is administered at a dose of about 400 mg once every 4 weeks.
- Compound A or a pharmaceutically acceptable salt, solvate or hydrate thereof, TNO155 or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., spartalizumab) are in separate formulations.
- a PD-1 inhibitor e.g., spartalizumab
- the combination of the invention is for simultaneous or sequential (in any order) administration.
- in another embodiment is a method for treating or preventing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the combination of the invention.
- the cancer is selected from non-small cell lung cancer, colorectal cancer, pancreatic cancer and a solid tumor.
- the cancer is colorectal cancer.
- the cancer is non-small cell lung cancer.
- the cancer is pancreatic cancer.
- the cancer is a solid tumor.
- the invention provides a combination of the invention for use in the manufacture of a medicament for treating a cancer selected from: non-small cell lung cancer, colorectal cancer, pancreatic cancer and a solid tumor.
- a pharmaceutical composition comprising the combination of the invention.
- the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients as described herein.
- Compound A is 1- ⁇ 6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl- 1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl ⁇ prop-2-en-1-one.
- Compound A is also known by the name “a (R) -1- (6- (4- (5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptan-2-yl) prop-2-en-1-one” .
- Compound A is a potent and selective KRAS G12C small molecule inhibitor that covalently binds to mutant Cys12, trapping KRAS G12C in the inactive GDP-bound state.
- Nonclinical data indicate that Compound A binds to KRAS G12C with low reversible binding affinity to the RAS SWII pocket, inhibiting downstream cellular signaling and proliferation specifically in KRAS G12C-driven cell lines but not KRAS wild-type (WT) or MEK Q56P mutant cell lines.
- Compound A showed deep and sustained target occupancy resulting in anti-tumor activity in different KRAS G12C mutant xenograft models.
- SHP2 inhibitor useful in combinations of the present invention is (3S, 4S) -8- (6-amino-5- ( (2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (TNO155) , or a pharmaceutically acceptable salt thereof.
- TNO155 is synthesized according to example 69 of WO2015/107495, which is incorporated by reference in its entirety.
- TNO155 is an orally bioavailable, allosteric inhibitor of Src homology-2 domain containing protein tyrosine phsophatase-2 (SHP2, encoded by the PTPN11 gene) , which transduces signals from activated receptor tyrosine kinases (RTKs) to downstream pathways, including the mitogen-activated protein kinase (MAPK) pathway.
- RTKs activated receptor tyrosine kinases
- MPK mitogen-activated protein kinase pathway
- SHP2 has also been implicated in immune checkpoint and cytokine receptor signaling.
- TNO155 has demonstrated efficacy in a wide range of RTK-dependent human cancer cell lines and in vivo tumor xenografts.
- the Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28/CTLA-4 family of T cell regulators.
- Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD-L2 (B7-DC) , that have been shown to downregulate T cell activation upon binding to PD-1.
- PD-L1 is abundant in a variety of human cancers.
- PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals.
- the interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, for example, a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous cells.
- Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well.
- compositions of the invention comprising a PD1-inhibitor (e.g., spartalizumab) may be particularly useful in the methods of the invention as KRAS G12C is associated with a higher rate of PD-L1 expression.
- a PD1-inhibitor e.g., spartalizumab
- Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof is further administered in combination with a PD-1 inhibitor.
- Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and TNO155, or a pharmaceutically acceptable salt thereof is further administered in combination with a PD-1 inhibitor.
- the PD-1 inhibitor is chosen from spartalizumab (PDR001, Novartis) , Nivolumab (Bristol-Myers Squibb) , Pembrolizumab (Merck & Co) , Pidilizumab (CureTech) , MEDI0680 (Medimmune) , REGN2810 (Regeneron) , TSR-042 (Tesaro) , PF-06801591 (Pfizer) , BGB-A317 (Beigene) , BGB-108 (Beigene) , INCSHR1210 (Incyte) , or AMP-224 (Amplimmune) .
- a particularly preferred PD-1 inhibitor for use according to the invention is spartalizumab.
- PDR001 is also known as spartalizumab, an anti-PD-1 antibody molecule described in US 2015/0210769, published on July 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof, ” incorporated by reference in its entirety.
- anti-PD-1 antibody molecules include the following:
- Nivolumab (Bristol-Myers Squibb) , also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or Nivolumab (clone 5C4) and other anti-PD-1 antibodies are disclosed in US 8,008,449 and WO 2006/121168, incorporated by reference in their entirety;
- Pembrolizumab (Merck & Co) , also known as Lambrolizumab, MK-3475, MK03475, SCH-900475, or Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2) : 134–44, US 8,354,509, and WO 2009/114335, incorporated by reference in their entirety;
- Pidilizumab (CureTech) , also known as CT-011.
- Pidilizumab and other anti-PD-1 antibodies are disclosed in Rosenblatt, J. et al. (2011) J Immunotherapy 34 (5) : 409-18, US 7,695,715, US 7,332,582, and US 8,686,119, incorporated by reference in their entirety;
- MEDI0680 Medimmune
- AMP-514 also known as AMP-514.
- MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9,205,148 and WO 2012/145493, incorporated by reference in their entirety;
- AMP-224 (B7-DCIg (Amplimmune) , e.g., disclosed in WO 2010/027827 and WO 2011/066342, incorporated by reference in their entirety;
- REGN2810 (Regeneron) ; PF-06801591 (Pfizer) ; BGB-A317 or BGB-108 (Beigene) ;
- INCSHR1210 (Incyte) , also known as INCSHR01210 or SHR-1210; TSR-042 (Tesaro) , also known as ANB011; and further known anti-PD-1 antibodies including 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, incorporated by reference in their entirety.
- the PD-1 inhibitor is an anti-PD-1 antibody molecule.
- the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US 2015/0210769, published on July 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof, ” incorporated by reference in its entirety.
- the anti-PD-1 inhibitor is spartalizumab, also known as PDR001.
- the anti-PD-1 antibody molecule is BAP049-Clone E or BAP049-Clone B.
- the anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1 (e.g., from the heavy and light chain variable region sequences of BAP049-Clone-E or BAP049-Clone-B disclosed in Table 1) , or encoded by a nucleotide sequence shown in Table 1.
- the CDRs are according to the Kabat definition (e.g., as set out in Table 1) .
- the CDRs are according to the Chothia definition (e.g., as set out in Table 1) .
- the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 1) .
- the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541) .
- 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., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.
- the anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 501, a VHCDR2 amino acid sequence of SEQ ID NO: 502, and a VHCDR3 amino acid sequence of SEQ ID NO: 503; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 510, a VLCDR2 amino acid sequence of SEQ ID NO: 511, and a VLCDR3 amino acid sequence of SEQ ID NO: 512, each disclosed in Table 1.
- VH heavy chain variable region
- VL light chain variable region
- the antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 525, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 526; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of 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 disclosed in Table 1.
- the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 506.
- the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 520, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 520.
- the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 516.
- the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 520.
- the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 516.
- the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507, or a nucleotide sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 507.
- the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517, or a nucleotide sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 521 or 517.
- the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507 and a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517.
- the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 508.
- the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 522.
- the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 518.
- the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 518.
- the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509, or a nucleotide sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 509.
- the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519, or a nucleotide sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 523 or 519.
- the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519.
- the antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0210769, incorporated by reference in its entirety.
- a combined inhibition of a checkpoint inhibitor (e.g., an inhibitor of TIM-3 described herein) with a TGF- ⁇ inhibitor is further combined with a PD-1 inhibitor and used to treat a cancer (e.g., a myelofibrosis) .
- the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose between about 100 mg to about 600 mg. e.g., about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 600 mg, about 200 mg to about 500 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, about 300 mg to about 600 mg, about 300 mg to about 500 mg, about 300 mg to about 400 mg, about 400 mg to about 600 mg, about 400 mg to about 500 mg, or about 500 mg to about 600 mg.
- a dose between about 100 mg to about 600 mg. e.g., about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 600 mg, about 200 mg to about 500 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, about 300 mg to about 600 mg, about 300 mg to about 500 mg, about
- the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg.
- the PD-1 inhibitor (e.g., spartalizumab) is administered once every four weeks.
- (e.g., spartalizumab) is administered once every three weeks.
- (e.g., spartalizumab) is administered intravenously.
- (e.g., spartalizumab) is administered over a period of about 20 minutes to 40 minutes (e.g., about 30 minutes) .
- the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose between about 300 mg to about 500 mg (e.g., about 400 mg) , intravenously, over a period of about 20 minutes to about 40 minutes (e.g., about 30 minutes) , once every two weeks.
- the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose between about 200 mg to about 400 mg (e.g., about 300 mg) , intravenously, over a period of about 20 minutes to about 40 minutes (e.g., about 30 minutes) , once every three weeks.
- the PD-1 inhibitor e.g., spartalizumab
- a TIM-3 inhibitor e.g., an anti-TIM3 antibody
- a TGF- ⁇ inhibitor e.g., NIS793
- each of the therapeutically active agents can be administered separately, simultaneously or sequentially, in any order.
- Compound A and/or TNO155 may be administered in an oral dose form.
- composition comprising a pharmaceutical combination of the invention and at least one pharmaceutically acceptable carrier.
- Compound A and combinations of the invention may be useful in the treatment of cancer.
- Compound A and combinations of the invention may be useful in the treatment of an cancer which is selected from the group consisting of lung cancer (such as lung adenocarcinoma and non-small cell lung cancer) , colorectal cancer (including colorectal adenocarcinoma) , pancreatic cancer (including pancreatic adenocarcinoma) , uterine cancer (including uterine endometrial cancer) , rectal cancer (including rectal adenocarcinoma) and a solid tumor.
- lung cancer such as lung adenocarcinoma and non-small cell lung cancer
- colorectal cancer including colorectal adenocarcinoma
- pancreatic cancer including pancreatic adenocarcinoma
- uterine cancer including uterine endometrial cancer
- rectal cancer including rectal adenocarcinoma
- a solid tumor a solid tumor.
- the cancer may be at an early, intermediate, late stage or metastatic cancer.
- the cancer is an advanced cancer.
- the cancer is a metastatic cancer.
- the cancer is a relapsed cancer.
- the cancer is a refractory cancer.
- the cancer is a recurrent cancer.
- the cancer is an unresectable cancer.
- the cancer may be at an early, intermediate, late stage or metastatic cancer.
- Compound A and combinations of the invention may also be useful in the treatment of solid malignancies characterized by mutations of RAS.
- Compound A and combinations of the invention may also be useful in the treatment of solid malignancies characterized by one or more mutations of KRAS, in particular G12C mutations in KRAS.
- the present invention provides the use of Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, alone or in combination with a second therapeutic agent which is selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor in therapy.
- a second therapeutic agent which is selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor in therapy.
- the present invention provides a triple combination consisting of Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor.
- the present invention provides a combination of the invention for use in therapy.
- the therapy or the therapy which the medicament is useful for is selected from a disease which may be treated by inhibition of RAS mutant proteins, in particular, KRAS, HRAS or NRAS G12C mutant proteins.
- the invention provides a method of treating a disease, which is treated by inhibition of a RAS mutant protein, in particular, a G12C mutant of either KRAS, HRAS or NRAS protein, in a subject in need thereof, wherein the method comprises the administration of a therapeutically effective amount of a compound of the invention, to the subject.
- the disease is selected from the afore-mentioned list, suitably non-small cell lung cancer, colorectal cancer and pancreatic cancer.
- the therapy is for a disease, which may be treated by inhibition of a RAS mutant protein, in particular, a G12C mutant of either KRAS, HRAS or NRAS protein.
- the disease is selected from the afore-mentioned list, suitably non-small cell lung cancer, colorectal cancer and pancreatic cancer, which is characterized by a G12C mutation in either KRAS, HRAS or NRAS.
- a cancer or a tumor in a subject comprising administering to a subject in need thereof a pharmaceutical composition comprising Compound A, or pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent as described herein.
- the present invention therefore provides a method of treating (e.g., one or more of reducing, inhibiting, or delaying progression) cancer or tumor in a patient in need thereof, wherein the method comprises administering to the patient in need thereof, a therapeutically active amount of Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, as a single agent or as combination therapy with a therapeutically active amount of one or two therapeutically active agents selected from TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor (e.g., sparatalizumab) , wherein the cancer is lung cancer (including lung adenocarcinoma and non-small cell lung cancer) , colorectal cancer (including colorectal adenocarcinoma) , pancreatic cancer (including pancreatic adenocarcinoma) , uterine cancer (including uterine endometrial cancer) , rectal cancer (including rectal adenocarcinoma) and a solid tumor, optional
- the subject or patient to be treated is selected from:
- KRAS G12C mutant solid tumor e.g. advanced (metastatic or unresectable) KRAS G12C mutant solid tumor
- the patient has received and failed standard of care therapy or is intolerant or ineligible to approved therapies
- KRAS G12C mutant NSCLC e.g., advanced (metastatic or unresectable) KRAS G12C mutant NSCLC
- KRAS G12C mutant NSCLC e.g., advanced (metastatic or unresectable) KRAS G12C mutant NSCLC
- KRAS G12C mutant CRC e.g., advanced (metastatic or unresectable) KRAS G12C mutant CRC
- standard of care therapy including a fluropyrimidine-, oxaliplatin-, and /or irinotecan-based chemotherapy.
- the Compound A, or pharmaceutically acceptable salt thereof, administered to the subject in need thereof is effective to treat the cancer.
- the second therapeutic agent or third therapeutic agent is TNO155, or a pharmaceutically acceptable salt thereof.
- the second therapeutic agent or third therapeutic agent is an immunomodulator, such as a PD-1 inhibitor.
- the PD-1 inhibitor is selected from PDR001, Nivolumab, Pembrolizumab, Pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, or AMP-224.
- the PD-1 inhibitor is PDR001 (spartazilumab) .
- Doses of Compound A when used alone or in combination therapy according to the present invention are designed to be pharmacologically active and result in an anti-tumor response.
- Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered at a therapeutically effective dose ranging from 200 to 1600 mg per day, e.g. from 400 to 1600 mg per day.
- the total daily dose of Compound A may be selected from 200, 300, 400, 600, 800, 1000, 1200 and 1600 mg.
- the total daily dose of Compound A may be administered continuously, on a QD (once a day) or BID (twice a day) regimen.
- TNO155 may be administered at a total daily dose ranging from 10 to 80 mg, or from 10 to 60 mg.
- the total daily dose of TNO155 may be selected from 10, 15, 20, 30, 40, 60 and 80 mg.
- the total daily dose of TNO155 may be administered continuously, QD (once a day) or BID (twice a day) on QD or BID on a 2 weeks on/1 week off schedule.
- the total daily dose of TNO155 may be administered continuously, QD (once a day) or BID (twice a day) on QD or BID on continuously (i.e. without a drug holiday) .
- Compound A is administered at a dose ranging from 200 to 1600 mg per day (e.g., 200, 300, 400, 600, 800, 1000, 1200 or 1600 mg) and TNO155 is administered at a dose ranging from 10 to 80 mg (0, 15, 20, 30, 40, 60 or 80 mg) , wherein Compound A is administered on a continuous schedule and TNO is administered either on a two week on/one week off schedule or on a continuous schedule.
- spartalizumab is administered at a dose of about 300 mg once every 3 weeks, or at a dose of about 400 mg once every 4 weeks. More preferably, spartalizumab is administered at a dose of about 300 mg once every 3 weeks (Q3W) , by injection (e.g., subcutaneously or intravenously) .
- Compound A is administered on a continuous schedule at a dose ranging from 200 to 1600 mg per day (e.g., 200, 300, 400, 600, 800, 1000, 1200 or 1600 mg) and spartalizumab is administered at a dose of about 300 mg once every 3 weeks, or at a dose of about 400 mg once every 4 weeks.
- a dose ranging from 200 to 1600 mg per day e.g., 200, 300, 400, 600, 800, 1000, 1200 or 1600 mg
- spartalizumab is administered at a dose of about 300 mg once every 3 weeks, or at a dose of about 400 mg once every 4 weeks.
- Compound A is administered on a continuous schedule at a dose ranging from 200 to 1600 mg per day (e.g., 200, 300, 400, 600, 800, 1000, 1200 or 1600 mg)
- TNO155 is administered either on a two week on/one week off schedule or on a continuous schedule at a dose ranging from 10 to 80 mg (0, 15, 20, 30, 40, 60 or 80 mg)
- spartalizumab is administered at a dose of about 300 mg once every 3 weeks or at a dose of about 400 mg once every 4 weeks.
- Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof may be administered either simultaneously with, or before or after, one or more (e.g., one or two) other therapeutic agents.
- Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
- the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more (e.g., one or two) therapeutic agents selected from Compound A, TNO155 and a PD-1 inhibitor, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
- one or more therapeutic agents selected from Compound A, TNO155 and a PD-1 inhibitor
- the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the present invention provides a pharmaceutical composition comprising a KRAS G12C inhibitor, such as Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and one or more (e.g., one or two) therapeutically active agents selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor.
- the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.
- solvates and hydrates are generally considered compositions.
- pharmaceutically acceptable carriers are sterile.
- the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
- the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories) , or in a liquid form (including without limitation solutions, suspensions or emulsions) .
- compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
- the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of:
- diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;
- lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;
- binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone;
- disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures
- the pharmaceutical compositions are capsules comprising the active ingredient only.
- Tablets may be either film coated or enteric coated according to methods known in the art.
- compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs, solutions or solid dispersion.
- Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable prepa-rations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
- Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
- compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
- Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
- Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
- compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier.
- Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
- transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
- compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
- topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, for-mulations well-known in the art.
- Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
- a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
- a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
- the invention provides a product comprising Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
- the therapy is the treatment of a disease or condition characterized by a KRAS, HRAS or NRAS G12C mutation.
- Products provided as a combined preparation include a composition comprising the compound of the present invention and one or more (e.g., one or two) therapeutically active agents selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor together in the same pharmaceutical composition, or Compound A, or a pharmaceutically acceptable salt, solvate or hydrate, thereof, and the other therapeutic agent (s) in separate form, e.g. in the form of a kit.
- a SHP2 inhibitor such as TNO155
- a pharmaceutically acceptable salt thereof e.g., a pharmaceutically acceptable salt thereof and a PD-1 inhibitor
- the other therapeutic agent (s) in separate form, e.g. in the form of a kit.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent (s) .
- the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above.
- the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof; TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor (e.g., spartalizumab) .
- the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
- An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
- the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
- the kit of the invention typically comprises directions for administration.
- the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the present invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the present invention and the other therapeutic agent) ; (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the present invention and the other therapeutic agent.
- the compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent.
- the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
- 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.
- the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
- a dosage is mentioned, it is intended to include a range around the specified value of plus or minus 10%, or plus or minus 5%.
- dosages refer to the amount of the therapeutic agent in its free form.
- TNO155 when a dosage of 20 mg of TNO155 is referred to, and TNO155 is used as its succinate salt, the amount of the therapeutic agent used is equivalent to 20 mg of the free form of TNO155.
- subject or “patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer.
- subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
- the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancers.
- treating comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease.
- treatment can be the diminishment of one or several symptoms of a disorder or partial or complete eradication of a disorder, such as cancer.
- the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
- composition therapy refers to the administration of two or more therapeutic agents to treat a condition or disorder described in the present disclosure (e.g., cancer) .
- Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients.
- such administration encompasses co-administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration.
- such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
- the combination therapy can provide “synergy” and prove “synergistic” , i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
- a synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
- alternation therapy a synergistic effect can be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes.
- synergistic effect refers to action of two therapeutic agents such as, for example, a compound TNO155 as a SHP2 inhibitor and Compound A, producing an effect, for example, slowing the symptomatic progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
- a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L.B., Clin. Pharmacokinet.
- pharmaceutical combination refers to either a fixed combination in one dosage unit form, or non-fixed combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
- terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
- phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
- pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
- Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts” , J. Pharm. Sci. 66: 1-19) .
- the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
- such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
- the pharmaceutically acceptable salt of TNO155 for example, is succ
- Compound A TNO155 and a PD-1 inhibitor
- Isotopically labeled compounds have one or more atoms replaced by an atom having a selected atomic mass or mass number.
- isotopes that can be incorporated into TNO155 and a PD-1 inhibitor include isotopes, where possible, of hydrogen, carbon, nitrogen, oxygen, and chlorine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 35 S, 36 Cl.
- the invention includes isotopically labeled TNO155 and a PD-1 inhibitor, for example into which radioactive isotopes, such as 3 H and 14 C, or non-radioactive isotopes, such as 2 H and 13 C, are present.
- Isotopically labelled TNO155 and a PD-1 inhibitor are useful in metabolic studies (with 14 C) , reaction kinetic studies (with, for example 2 H or 3 H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
- PET positron emission tomography
- SPECT single-photon emission computed tomography
- Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagents. Further, substitution with heavier isotopes, particularly deuterium (i.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of either Compound A, TNO155 or a PD-1 inhibitor. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor.
- isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in TNO155 or a PD-1 inhibitor is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated deuterium atom) , at least 4000 (60%deuterium incorporation) , at least 4500 (67.5%deuterium incorporation) , at least 5000 (75%deuterium incorporation) , at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at least 6333.3 (95%deuterium incorporation) , at least 6466.7 (97%deuterium incorporation) , at least 6600 (99%deuterium incorporation) , or at least 6633.3 (99.5%deuterium incorporation) .
- a methyl group e.g. on the indazolyl ring, may be deuterated or perdeuterated.
- Example 1 Preparation of 1- ⁇ 6- [ (4 M ) -4- (5-Chloro-6-methyl-1 H -indazol-4-yl) -5-methyl-3- (1- methyl-1 H -indazol-5-yl) -1 H -pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl ⁇ prop-2-en-1-one (Compound A)
- Compound A is also known by the name “a (R) -1- (6- (4- (5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptan-2-yl) prop-2-en-1-one” .
- Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using electrospray, chemical and electron impact ionization methods with a range of instruments of the following configurations: Waters Acquity UPLC with Waters SQ detector or Mass spectra were acquired on LCMS systems using ESI method with a range of instruments of the following configurations: Waters Acquity LCMS with PDA detector. [M+H] + refers to the protonated molecular ion of the chemical species.
- NMR spectra were run with Bruker Ultrashield TM 400 (400 MHz) , Bruker Ultrashield TM 600 (600 MHz) and Bruker Ascend TM 400 (400 MHz) spectrometers, both with and without tetramethylsilane as an internal standard. Chemical shifts ( ⁇ -values) are reported in ppm downfield from tetramethylsilane, spectra splitting pattern are designated as singlet (s) , doublet (d) , triplet (t) , quartet (q) , multiplet, unresolved or more overlapping signals (m) , broad signal (br) . Solvents are given in parentheses. Only signals of protons that are observed and not overlapping with solvent peaks are reported.
- Phase separator Biotage –Isolute phase separator – (Part number: 120-1908-F for 70 mL and part
- X-ray powder diffraction (XRPD) patterns described herein were obtained using a Bruker Advance D8 in reflection geometry. Powder samples were analyzed using a zero background Si flat sample holder. The radiation was Cu K ⁇ Patterns were measured between 2° and 40° 2theta.
- Microwave All microwave reactions were conducted in a Biotage Initiator, irradiating at 0–400 W from a magnetron at 2.45 GHz with Robot Eight/Robot Sixty processing capacity, unless otherwise stated.
- UPLC-MS-1 Acquity HSS T3; particle size: 1.8 ⁇ m; column size: 2.1 x 50 mm; eluent A: H 2 O +0.05%HCOOH + 3.75 mM ammonium acetate; eluent B: CH 3 CN + 0.04%HCOOH; gradient: 5 to 98%B in 1.40 min then 98%B for 0.40 min; flow rate: 1 mL/min; column temperature: 60°C.
- UPLC-MS-3 Acquity BEH C18; particle size: 1.7 ⁇ m; column size: 2.1 x 50 mm; eluent A: H 2 O +4.76%isopropanol + 0.05%HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05%HCOOH; gradient: 1 to 98%B in 1.7 min then 98%B for 0.1 min min; flow rate: 0.6 mL/min; column temperature: 80°C.
- UPLC-MS-4 Acquity BEH C18; particle size: 1.7 ⁇ m; column size: 2.1 x 100 mm; eluent A: H 2 O +4.76%isopropanol + 0.05%HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05%HCOOH; gradient: 1 to 60%B in 8.4 min then 60 to 98%B in 1 min; flow rate: 0.4 mL/min; column temperature: 80°C.
- UPLC-MS-6 Acquity BEH C18; particle size: 1.7 ⁇ m; column size: 2.1 x 50 mm; eluent A: H 2 O +0.05%HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05%HCOOH; gradient: 5 to 98%B in 1.7 min then 98%B for 0.1 min; flow rate: 0.6 mL/min; column temperature: 80°C.
- C-SFC-1 column: Amylose-C NEO 5 ⁇ m; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40°C; back pressure: 120 bar.
- C-SFC-3 column: Chiralpak AD-H 5 ⁇ m; 100 x 4.6 mm; mobile phase; flow rate: 3 mL/min; column temperature: 40°C; back pressure: 1800 psi.
- All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to prepare the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. Furthermore, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.
- the structures of all final products, intermediates and starting materials are confirmed by standard analytical spectroscopic characteristics, e.g., MS, IR, NMR.
- the absolute stereochemistry of representative examples of the preferred (most active) atropisomers has been determined by analyses of X-ray crystal structures of complexes in which the respective compounds are bound to the KRASG12C mutant. In all other cases where X-ray structures are not available, the stereochemistry has been assigned by analogy, assuming that, for each pair, the atropoisomer exhibiting the highest activity in the covalent competition assay has the same configuration as observed by X-ray crystallography for the representative examples mentioned above.
- the absolute stereochemistry is assigned according to the Cahn–Ingold–Prelog rule.
- Step C. 1 tert-butyl 6- (tosyloxy) -2-azaspiro [3.3] heptane-2-carboxylate ( Intermediate C2 )
- Step C. 3 tert-butyl 6- (3, 5-dibromo-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate
- Step C. 4 tert-butyl 6- (3-bromo-5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (In termediate C3)
- the reaction mixture was poured into sat. aq. NH 4 Cl solution (4 L) and extracted with DCM (10 L) .
- the separated aqueous layer was re-extracted with DCM (5 L) and the combined organic layers were concentrated under vacuum.
- the crude product was dissolved in 1, 4-dioxane (4.8 L) at 60 °C, then water (8.00 L) was added dropwise slowly.
- the resulting suspension was cooled to 17 °C and stirred for 30 min.
- the solid was filtered, washed with water, and dried under vacuum to give the title compound.
- Step C. 5 tert-butyl 6- (3-bromo-4-iodo-5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (Intermediate C4)
- Step C. 6 tert-butyl 6- (3-bromo-4- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (Intermediate C1)
- Step D. 2 3-bromo-2-chloro-1, 4-dimethyl-5-nitrobenzene
- Step D. 4 3-bromo-4-chloro-2, 5-dimethylbenzenediazonium tetrafluoroborate
- Step D. 6 4-bromo-5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
- Step D. 7 5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (Intermediate D. 1)
- reaction mixture was filtered through diatomite and the filter cake was washed with EtOAc (1.50 L x 3) .
- the mixture was concentrated under vacuum to give a black oil which was purified by normal phase chromatography (eluent: Petroleum ether/EtOAc from 100/1 to 10/1) to give the desired product as brown oil.
- the residue was suspended in petroleum ether (250 mL) for 1 h to obtain a white precipitate. The suspension was filtered, dried under vacuum to give the title compound as a white solid.
- Step 1 Tert-butyl 6- (4- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate
- tert-butyl 6- (3-bromo-4- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (Intermediate C1, 10 g, 16.5 mmol) , (1-methyl-1H-indazol-5-yl) boronic acid (6.12 g, 33.1 mmol)
- Step 2 5-Chloro-6-methyl-4- (5-methyl-3- (1-methyl-1H-indazol-5-yl) -1- (2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -1H-indazole
- Step 3 1- (6- (4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptan-2-yl) prop-2-en-1-one
- the reaction mixture was stirred at RT under nitrogen for 15 min.
- the RM was poured into a sat. aq. NaHCO 3 solution and extracted with CH 2 Cl 2 (x3) .
- the combined organic layers were dried (phase separator) and concentrated.
- the crude residue was diluted with THF (60 mL) and LiOH (2N, 15.7 mL, 31.5 mmol) was added.
- the mixture was stirred at RT for 30 min until disappearance (UPLC) of the side product resulting from the reaction of the acryloyl chloride with the free NH group of the indazole then was poured into a sat. aq. NaHCO 3 solution and extracted with CH 2 Cl 2 (3x) .
- Example 1 a (R) -1- (6- (4- (5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptan-2-yl) prop-2-en-1-one as the second eluting peak (white powder) :
- 1 H NMR 600 MHz, DMSO-d 6 ) ⁇ 13.1 (s, 1H) , 7.89 (s, 1H) , 7.59 (s, 1H) , 7.55 (s, 1H) , 7.42 (m, 2H) , 7.30 (d, 1H) , 6.33 (m, 1H) , 6.12 (m, 1H) , 5.68 (m, 1H) , 4.91 (m, 1H) , 4.40 (s, 1H) , 4.33 (s, 1H) , 4.11 (s, 1H
- Crystalline forms of Compound A such as the ones described below are particularly suitable in the methods and uses of the invention.
- Example 2a Crystalline isopropyl alcohol (IPA) solvate of Compound A and crystalline hydrate (Modification HA) form of Compound A
- Crystalline hydrate (Modification HA) form of Compound A was analysed by XRPD and the most characteristic peaks are shown in the Table below.
- the most characteristic peaks of the XRPD pattern of the crystalline hydrate (Modification HA) form may be selected from one, two, three or four peaks having an angle of refraction 2 ⁇ values (CuK ⁇ ) selected from the group consisting of 8.2°, 11.6°, 12.9°and 18.8°.
- the most characteristic peaks of the XRPD pattern of the crystalline IPA solvate form may be selected from one, two, or three peaks having an angle of refraction 2 ⁇ values (CuK ⁇ ) selected from the group consisting of 7.5°, 12.5° and 17.6°.
- Example 2b Crystalline ethanol (EtOH) solvate of Compound A and crystalline hydrate (Modification HA) form of Compound A
- the most characteristic peaks of the XRPD pattern of the crystalline ethanol solvate form may be selected from one, two, or three or four peaks having an angle of refraction 2 ⁇ values (CuK ⁇ ) selected from the group consisting of 7.9°, 12.7°, 18.2° and 23.1°.
- Example 2c alternative preparation of crystalline hydrate (Modification HA) preparation
- Example 2d crystalline propylene glycol solvate preparation and hydrate (Modification HA) preparation
- the most characteristic peaks of the XRPD pattern of the crystalline propylene glycol solvate form may be selected from one, two, or three or four peaks having an angle of refraction 2 ⁇ values (CuK ⁇ ) selected from the group consisting of 7.3°, 13.2°, 18.0° and 25.5°.
- Compound A demonstrated potent and selective target occupancy.
- Compound A selectively inhibited downstream effector protein recruitment to KRAS G12C, but not to any other RAS wild-type isoform.
- Compound A inhibited KRAS-driven oncogenic signaling and proliferation specifically in KRAS G12C-mutant cell lines, but not KRAS WT or MEK Q56P mutant cell lines.
- KRAS G12C mutant xenograft models in mice PD responses correlated with Compound A exposure in blood.
- free tumor KRAS G12C levels were robustly reduced in a dose-dependent manner and correlated with inhibition of tumor expression of the MAPK pathway target gene, DUSP-6.
- Example 4 In vitro combinations of Compound A with TNO155 in KRASG12C- mutated NSCLC cell lines
- NSCLC non-small-cell lung carcinoma
- the indicated KRAS G12C-mutated human NSCLC cell lines were dispensed into 384-well tissue culture plates.
- the matrices in Figure 1 report the percentage Growth Inhibition (GI) for each treatment as compared to DMSO-treated cells, with darker colors denoting greater cell growth inhibition and/or cell kill.
- the data was processed using classical synergy models (Loewe, Bliss) .
- the synergy scores for the Compound A/TNO155 combinations for the following cell lines were as follows. NCI-H2122: 16.7; HCC-1171: 9.7; NCI-H1373: 6.9. Synergy scores above 2 indicate a synergistic level.
- Example 5 Anti-tumor efficacy of Compound A alone and in combination with TNO155 in Lu99 KRASG12C lung carcinoma mouse xenograft models
- a heterozygous KRASG12C lung cancer xenograft model named Lu99, was used in an efficacy study in mice to study the efficacy and tolerability of Compound A, TNO155 used as single agents, and in combination.
- mice Male nude mice (Charles River Laboratories, Crl: NU (NCr) -Foxn1nu –Homozygous) .
- the animals were housed in a 12 h light/dark cycle facility and had access to sterilized food and water ad libitum. Animals were allowed to accommodate at least for 7 days.
- the Lu99 human cell line originates from a Lung giant cell carcinoma of a 63 year-old male patient [Yamada et al, 1985] . It carries the allele NM_033360.4 (KRAS) : c. 34G>T and consequently a heterozygous KRAS Gly12Cys mutation. Lu99 cells were grown in sterile conditions in a 37°C incubator with 5%CO2 for two weeks. The cells were kept in RPMI media supplemented with 10%FCS, 2mM L-Glutamin, 1mM sodium pyruvate and 10mM HEPES, and split 1: 6 every 3 days.
- Cells were tested negative for mycoplasma and murine viruses in 2012 (Radil case number: 8270-2012) . On the day of injection, cells were harvested after 8 passages in total, including passages from the vendor. Cells were resuspended in 50%HBSS and 50%Matrigel at a final concentration of 10.10 6 cells/ml.
- mice were then treated orally at with vehicle, Compound A at 100 mg/kg once daily, TNO155 at 10 mg/kg twice daily, or a combination of Compound A at 100 mg/kg once daily and TNO155 at 10 mg/kg twice daily.
- Compound A and TNO155 were each formulated as a suspension in 0.1%Tween 80 (Fisher Scientific AG #BP338-500) and 0.5%Methylcellulose in water.
- the control group received a solution of 0.1%Tween 80 (Fisher Scientific AG #BP338-500) and 0.5%Methylcellulose in water.
- the treatment period was between 9 to 28 days, depending on the groups. Animals treated with vehicle were terminated at day 9 and TNO155 treated animals at day 14 as their tumor volume reached the authorized limit. Animals treated with Compound A or the combination of Compound A and TNO155 were treated for 28 days, and then kept for 5 more days without any treatment.
- Example 6 Anti-tumor efficacy of Compound A alone and in combination with different schedules of TNO155 in Lu99 KRASG12C lung carcinoma mouse xenograft models
- mice An in vivo combination study of Compound A with different schedules of TNO155 was conducted in the KRAS G12C-mutated Lu99 xenograft model in female nude mice.
- Mice were injected subcutaneously with Lu99 human NSCLC cells to induce xenograft tumors and randomized into treatment groups when the mean tumor volume reached ⁇ 200 mm 3 .
- Mice were treated orally with vehicle, Compound A at 100 mg/kg once daily, TNO155 at 10 mg/kg twice daily continuous, or a combination of Compound A at 100 mg/kg once daily and TNO155 at 10 mg/kg twice daily on a continuous or two weeks on one week off schedule.
- the treatment period was between 14 to 35 days, depending on the groups. Animals treated with vehicle were terminated at day 14.
- TNO155 and Compound A treated animals were terminated at day 21. Animals treated with the combination of Compound A and TNO155 were treated for 35 days. Tumor volumes were recorded and are represented as mean ⁇ SEM for each group. Anti-tumor response of treatment groups vs. vehicle group was calculated at day 14 as %T/C or %regression. Daily dosing with Compound A at 100 mg/kg induced tumor regression for approximately two weeks, followed by tumor relapse while treatment was still ongoing. TNO155 given continuously at 10 mg/kg twice daily led to slight tumor growth delay compared to the vehicle group. The combination of Compound A with TNO155 significantly improved the sustainability of response and time to relapse seen with Compound A as a single agent. Hereby, the combination effect was the same regardless whether TNO155 was given at a continuous schedule or a two weeks on, one week off schedule.
- Example 7 Anti-tumor efiicacy of Compound A alone and in combination with TNO155 in Lu99 KRASG12C colorectal mouse xenograft models
- mice Female nude mice were implanted subcutaneously with tumor fragments from each PDX model. Individual mice were assigned to treatment groups for dosing once their tumor volume reached 200-250mm 3 . One animal per PDX model was assigned to each treatment arm. Mice were left untreated (control) , or were treated orally with Compound A at 100 mg/kg daily or a combination of Compound A at 100 mg/kg daily and TNO155 at 10 mg/kg twice daily.
- the end of study per model was defined as minimum of 28 days treatment, or duration for untreated tumor to reach 1500mm 3 , or duration for two doublings of untreated tumor, whichever was slower. Tumor volumes were recorded and are represented as %tumor volume change ⁇ SEM for each group. Daily dosing with Compound A led to regression of one PDX model and to a slight to moderate tumor growth delay in some PDX models. The combination of Compound A with TNO155 improved the response in all PDX models, ranging from strong tumor growth inhibition to tumor regression (see Figure 4) .
- Example8 Study of Compound A in patients with advanced solid tumors harboring the KRAS G12C mutation
- a study to assess the safety and tolerability of Compound A single agent and Compound A in combination with TNO155, Compound A in combination with spartalizumab, and Compound A in combination with TNO155 and spartalizumab, and to identify the maximum tolerated dose and/or recommended dose and regimen for future studies is carried out.
- the study is also carried out to evaluate the anti-tumor activity of the study treatments and to evaluate the immunogenicity of spartalizumab when dosed in combination with Compound A and /or TNO155.
- the study is conducted in adult patients with advanced solid tumors who harbor the KRAS G12C mutation.
- advanced (metastatic or unresectable) non-small cell lung cancer patients who harbor the KRAS G12C mutation and who are in the second or third line treatment setting will be enrolled.
- Additional groups of advanced colorectal cancer patients who have the KRAS G12C mutation and who have failed standard of care therapy (i.e. fluropyrimidine-, oxaliplatin-, and /or irinotecan-based chemotherapy) will also be enrolled in the Compound A single agent and Compound A plus TNO155 expansion groups.
- Compound A is administered orally (p.o. ) QD or BID continuously on a 21-day cycle.
- Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered at a therapeutically effective dose ranging from 200 to 1600 mg per day, e.g. from 400 to 1600 mg per day.
- the total daily dose of Compound A may be selected from 200, 300, 400, 600, 800, 1000, 1200 and 1600 mg.
- the total daily dose of Compound A may be administered continuously, on a QD (once a day) or BID (twice a day) regimen.
- TNO155 is administered p.o. QD or BID in a 2 week on/1 week off schedule or continuously.
- TNO155 may be administered at a total daily dose ranging from 10 to 80 mg, or from 10 to 60 mg.
- the total daily dose of TNO155 may be selected from 10, 15, 20, 30, 40, 60 and 80 mg.
- the total daily dose of TNO155 may be administered continuously, QD (once a day) or BID (twice a day) on QD or BID on a 2 weeks on/1 week off schedule.
- the total daily dose of TNO155 may be administered continuously, QD (once a day) or BID (twice a day) on QD or BID on continuously (i.e. without a drug holiday) .
- Spartalizumab is administered intravenously on a 21-day cycle at a dose of about 300 mg once every 3 weeks, or at a dose of about 400 mg once every 4 weeks.
- Efficacy of the therapeutic methods of the invention may be determined by methods well known in the art, e.g. determining Best Overall Response (BOR) , Overall Response Rate (ORR) , Duration of Response (DOR) , Disease Control Rate (DCR) , Progression Free Survival, (PFS) and Overall Survival (OS) per RECIST v. 1.1.
- BOR Best Overall Response
- ORR Overall Response Rate
- DCR Disease Control Rate
- PFS Progression Free Survival
- OS Overall Survival
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Abstract
It relates to a pharmaceutical combination comprising a KRAS G12C inhibitor and one or more therapeutically active agents selected from TNO155 and a PD-1 inhibitor; pharmaceutical compositions comprising the same; and methods of using such combinations and compositions in the treatment or prevention of cancers.
Description
The present invention relates to a KRAS G12C inhibitor and its uses in treating cancer (e.g. non-small cell lung cancer, colorectal cancer, pancreatic cancer or a solid tumor) alone and in combination with one or two additional therapeutically active agents. The present invention relates to a pharmaceutical combination comprising (i) a KRAS G12C inhibitor, such as Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a second therapeutic agent which is a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, or a PD-1 inhibitor. The present invention also relates to a triple combination comprising a KRAS G12C inhibitor, such as Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a second therapeutic agent which is a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor. The present invention also relates to pharmaceutical compositions comprising the same; and methods of using such combinations and compositions in the treatment or prevention of a cancer or a solid tumor.
Despite the recent successes of targeted therapies and immunotherapies, metastatic cancer remains largely incurable.
The KRAS oncoprotein is a GTPase with an essential role as regulator of intracellular signaling pathways, such as the MAPK, PI3K and Ral pathways, which are involved in proliferation, cell survival and tumorigenesis. Oncogenic activation of KRAS occurs predominantly through missense mutations in codon 12. KRAS gain-of-function mutations are found in approximately 30%of all human cancers. KRAS G12C mutation is a specific sub-mutation, prevalent in approximately 13%of lung adenocarcinomas, 4% (3-5%) of colon adenocarcinomas and a smaller fraction of other cancer types,
In normal cells, KRAS alternates between inactive GDP-bound and active GTP-bound states. Mutations of KRAS at codon 12, such as G12C, impair GTPase-activating protein (GAP) -stimulated GTP hydrolysis. In that case, the conversion of the GTP to the GDP form of KRAS G12C is therefore very slow. Consequently, KRAS G12C shifts to the active, GTP-bound state, thus driving oncogenic signaling.
Lung cancer remains the most common cancer type worldwide and the leading cause of cancer deaths in many counties, including the United States. NSCLC accounts for about 85%of all lung cancer diagnoses. KRAS mutations are detected in approximately 25%of patients with lung adenocarcinomas (Sequist et al 2011) . They are most commonly seen at codon 12, with KRAS G12C mutations being most common (40%overall) in both adenocarcinoma and squamous NSCLC (Liu et al 2020) . The presence of KRAS mutations is prognostic of poor survival and has been associated with reduced responsiveness to EGFR TKI treatment.
There are no approved targeted therapies currently available for patients with KRAS G12C mutant NSCLC and standard of care treatment consists of platinum-based chemotherapy and immune checkpoint inhibitors. Immunotherapy for NSCLC with immune checkpoint inhibitors has demonstrated promise, with some NSCLC patients experiencing durable disease control for years. However, such long-term non-progressors are uncommon, and treatment strategies that can increase the proportion of patients responding to and achieving lasting remission with therapy are urgently needed.
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer related death in the United States. The number of new cases of CRC was approximately 150,000 in the USA in 2019, whereas more than 300,000 patients are estimated to be diagnosed with CRC in the EU in 2020 (European Cancer Information System 2020) . Despite observed improvements in the overall incidence rate of CRC, the incidence in patients younger than 50 years has been increasing in recent years (Bailey et al 2015) with the authors estimating that the incidence rates for colon and rectal cancers may increase by 90%and about 124%, respectively, for patients 20-34 years of age by 2030. Systemic therapy for metastatic CRC includes various agents used alone or in combination, including chemotherapies such as 5-Fluorouracil/leucovorin, capecitabine, oxaliplatin, and irinotecan; anti-angiogenic agents such as bevacizumab and ramucirumab; anti-EGFR agents including cetuximab and panitumumab for KRAS/NRAS wild-type cancers; and immunotherapies including nivolumab and pembrolizumab. Despite multiple active therapies, however, metastatic CRC remains incurable.
While CRCs that are deficient in mismatch repair (MSI-high) exhibit high response rates to immune checkpoint inhibitor therapy, mismatch repair proficient CRCs do not. Since KRAS-mutant CRCs are typically mismatch repair proficient and are not candidates for anti-EGFR therapy, this subtype of CRC is particularly in need of improved therapies.
Tumor profiling data show that there is a subset of solid tumors other than NSCLC and CRC that harbor KRAS G12C mutations. KRAS G12C is present in approximately 1-2%of malignant solid tumors, including approximately 1%of all pancreatic cancers (Biernacka et al 2016, Zehir et al 2017) .
Several targeted therapies are at present in clinical testing aiming to address patients with KRAS mutations by inhibiting the RAS pathway. However, the benefit of these therapies for tumors harboring KRAS G12C mutations remains uncertain at present, as not all patients responded and in several instances, the duration of the reported responses were short.
There thus remains a high unmet medical need for new treatment options for patients suffering from cancer, including advanced and/or metastatic cancer including NSCLC, colorectal cancer, pancreatic cancer and a solid tumor, especially when the cancer or solid tumor harbors a KRAS G12C mutation. It is also important to provide a potentially beneficial novel investigative therapy for incurable disease, especially for patients with KRAS G12C mutant tumors who have already received and failed standard of care therapy for their indication or are intolerant or ineligible to approved therapies and have therefore limited treatment options.
Figure 1: Combinations of Compound A and TNO155 are synergistic in KRASG12C-mutated NSCLC cell lines.
Figure 2: Compound A alone and in combination with TNO155 shows anti-tumor efficacy in a Lu99 KRASG12C lung carcinoma mouse xenograft models.
Figure 3: A combination of Compound A with TNO155 is efficacious both when TNO155 is administered continuously (abbreviated as “cont. ” in Figure 3) and administered two weeks on and one week off.
Figure 4: Efficacy of a combination of Compound A and TNO155 in CRC xenograft models.
SUMMARY OF THE INVENTION
The data and the Examples herein show that Compound A alone and in combination with another therapeutically active agent which is selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, a PD-1 inhibitor, and combinations thereofmay be useful in treating cancer, for example, cancers driven by KRASG12C mutations. Targeted inhibition of KRAS G12C via Compound A may result in robust antitumor responses. Compound A may provide combination benefit in patients that have for instance acquired resistance to KRASG12C inhibitor by reactivation of RTK-MAPK pathway bypassing KRASG12C to signal through WT KRAS.
In KRASG12C NSCLC cell lines, the combination of Compound A with the SHP2 inhibitor TNO155 results in more sustained RAS pathway inhibition than Compound A alone. In addition, this combination leads to improved tumor cell growth inhibition in several cell lines. It is also shown herein that the combination of Compound A with TNO155 significantly improved the sustainability of response and time to relapse seen with Compound A as a single agent and TNO155 as single agent.
Compound A may induce a pro-inflammatory microenvironment that enhances the efficacy of anti-PD-1 therapies such as spartalizumab. Combinations of Compound A with spartalizumab may thus result in improved anti-tumor activity compared to either single agent.
Adding the SHP2 inhibitor TNO155 to Compound A plus spartalizumab may further decrease intracellular PD-1 signaling and lead to a less suppressive tumor microenvironment allowing for an improved immune response and better anti-tumor activity compared to single agent treatment or doublet combinations
The present invention therefore provides a KRAS G12 C inhibitor which is 1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one, (Compound A) , or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, as described herein. The present invention therefore also provides a pharmaceutical combination comprising a KRAS G12C inhibitor, such as Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a second therapeutically active agents selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor. In addition to these combinations, the present invention also provides a triple combination consisting of Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor.
The present invention also provides a pharmaceutical combination comprising
(i) 1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one, having the structure
or a pharmaceutically acceptable salt thereof,
and
(ii) (3S, 4S) -8- (6-amino-5- ( (2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (TNO155) , having the structure:
or a pharmaceutically acceptable salt thereof.
The present invention provides a pharmaceutical combination comprising:
1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one (Compound A) , or a pharmaceutically acceptable salt thereof and
(ii) a PD-1 inhibitor
The present invention provides a pharmaceutical combination comprising
(i) 1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one (Compound A) , or a pharmaceutically acceptable salt thereof,
(ii) TNO155, or a pharmaceutically acceptable salt thereof,
and
(iii) a PD-1 inhibitor.
It will be understood that reference herein to “a combination of the invention” or “the combination (s) of the invention” is intended to include each of these pharmaceutical combinations individually and to all of these combinations as a group.
The present invention provides these pharmaceutical combinations for use in treating a cancer as described herein.
In embodiments of the invention, the PD-1 inhibitor is chosen from PDR001 (spartalizumab; Novartis) , Nivolumab (Bristol-Myers Squibb) , Pembrolizumab (Merck & Co) , Pidilizumab (CureTech) , MEDI0680 (Medimmune) , REGN2810 (Regeneron) , TSR-042 (Tesaro) , PF-06801591 (Pfizer) , BGB-A317 (Beigene) , BGB-108 (Beigene) , INCSHR1210 (Incyte) , or AMP-224 (Amplimmune) .
In embodiments of the invention, the PD-1 inhibitor is PDR001 (spartalizumab) .
In embodiments of the invention, the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose of about 300-400 mg.
In embodiments of the invention, the PD-1 inhibitor (e.g., spartalizumab) is administered once every 3 weeks or once every 4 weeks.
In embodiments of the invention, the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose of about 300 mg once every 3 weeks.
In embodiments of the invention, the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose of about 400 mg once every 4 weeks.
In another embodiment of the combination of the invention, Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, TNO155 or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., spartalizumab) are in separate formulations.
In another embodiment, the combination of the invention is for simultaneous or sequential (in any order) administration.
In another embodiment is a method for treating or preventing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the combination of the invention.
In embodiments of the methods of the invention, the cancer is selected from non-small cell lung cancer, colorectal cancer, pancreatic cancer and a solid tumor.
In a further embodiment of the method, the cancer is colorectal cancer.
In a further embodiment of the method, the cancer is non-small cell lung cancer.
In a further embodiment of the method, the cancer is pancreatic cancer.
In a further embodiment of the method, the cancer is a solid tumor.
In a further embodiment, the invention provides a combination of the invention for use in the manufacture of a medicament for treating a cancer selected from: non-small cell lung cancer, colorectal cancer, pancreatic cancer and a solid tumor. In another embodiment is a pharmaceutical composition comprising the combination of the invention.
In a further embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients as described herein.
KRAS G12C inhibitor Compound A
Compound A is 1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl- 1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one. Compound A is also known by the name “a (R) -1- (6- (4- (5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptan-2-yl) prop-2-en-1-one” .
The synthesis of Compound A and crystalline forms thereof are as described in the Examples below. Crystalline forms of Compound A, e.g., as described in the Examples, are also particularly useful in the methods and uses of the present invention.
The structure of Compound A is as follows:
Alternatively, the structure of Compound A may be drawn as follows:
Compound A is a potent and selective KRAS G12C small molecule inhibitor that covalently binds to mutant Cys12, trapping KRAS G12C in the inactive GDP-bound state. Nonclinical data indicate that Compound A binds to KRAS G12C with low reversible binding affinity to the RAS SWII pocket, inhibiting downstream cellular signaling and proliferation specifically in KRAS G12C-driven cell lines but not KRAS wild-type (WT) or MEK Q56P mutant cell lines. Compound A showed deep and sustained target occupancy resulting in anti-tumor activity in different KRAS G12C mutant xenograft models.
SHP2 inhibitor
An example of a SHP2 inhibitor useful in combinations of the present invention is (3S, 4S) -8- (6-amino-5- ( (2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (TNO155) , or a pharmaceutically acceptable salt thereof. TNO155 is synthesized according to example 69 of WO2015/107495, which is incorporated by reference in its entirety.
TNO155 is an orally bioavailable, allosteric inhibitor of Src homology-2 domain containing protein tyrosine phsophatase-2 (SHP2, encoded by the PTPN11 gene) , which transduces signals from activated receptor tyrosine kinases (RTKs) to downstream pathways, including the mitogen-activated protein kinase (MAPK) pathway. SHP2 has also been implicated in immune checkpoint and cytokine receptor signaling. TNO155 has demonstrated efficacy in a wide range of RTK-dependent human cancer cell lines and in vivo tumor xenografts.
PD1-inhibitors
The Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28/CTLA-4 family of T cell regulators. Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD-L2 (B7-DC) , that have been shown to downregulate T cell activation upon binding to PD-1. PD-L1 is abundant in a variety of human cancers.
PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals. The interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, for example, a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous cells. Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well.
Pharmaceutical combinations of the invention comprising a PD1-inhibitor (e.g., spartalizumab) may be particularly useful in the methods of the invention as KRAS G12C is associated with a higher rate of PD-L1 expression.
In certain embodiments, Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, is further administered in combination with a PD-1 inhibitor. In certain embodiments, Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and TNO155, or a pharmaceutically acceptable salt thereof, is further administered in combination with a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is chosen from spartalizumab (PDR001, Novartis) , Nivolumab (Bristol-Myers Squibb) , Pembrolizumab (Merck & Co) , Pidilizumab (CureTech) , MEDI0680 (Medimmune) , REGN2810 (Regeneron) , TSR-042 (Tesaro) , PF-06801591 (Pfizer) , BGB-A317 (Beigene) , BGB-108 (Beigene) , INCSHR1210 (Incyte) , or AMP-224 (Amplimmune) . A particularly preferred PD-1 inhibitor for use according to the invention is spartalizumab.
PDR001 is also known as spartalizumab, an anti-PD-1 antibody molecule described in US 2015/0210769, published on July 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof, ” incorporated by reference in its entirety.
Further anti-PD-1 antibody molecules include the following:
Nivolumab (Bristol-Myers Squibb) , also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or
Nivolumab (clone 5C4) and other anti-PD-1 antibodies are disclosed in US 8,008,449 and WO 2006/121168, incorporated by reference in their entirety;
Pembrolizumab (Merck & Co) , also known as Lambrolizumab, MK-3475, MK03475, SCH-900475, or
Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2) : 134–44, US 8,354,509, and WO 2009/114335, incorporated by reference in their entirety;
Pidilizumab (CureTech) , also known as CT-011. Pidilizumab and other anti-PD-1 antibodies are disclosed in Rosenblatt, J. et al. (2011) J Immunotherapy 34 (5) : 409-18, US 7,695,715, US 7,332,582, and US 8,686,119, incorporated by reference in their entirety;
MEDI0680 (Medimmune) , also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9,205,148 and WO 2012/145493, incorporated by reference in their entirety;
AMP-224 (B7-DCIg (Amplimmune) , e.g., disclosed in WO 2010/027827 and WO 2011/066342, incorporated by reference in their entirety;
REGN2810 (Regeneron) ; PF-06801591 (Pfizer) ; BGB-A317 or BGB-108 (Beigene) ;
INCSHR1210 (Incyte) , also known as INCSHR01210 or SHR-1210; TSR-042 (Tesaro) , also known as ANB011; and further known anti-PD-1 antibodies including 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, incorporated by reference in their entirety.
Exemplary PD-1 Inhibitors
In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US 2015/0210769, published on July 30, 2015, entitled “Antibody Molecules to PD-1 and Uses Thereof, ” incorporated by reference in its entirety. In one embodiment, the anti-PD-1 inhibitor is spartalizumab, also known as PDR001. In some embodiments, the anti-PD-1 antibody molecule is BAP049-Clone E or BAP049-Clone B.
In embodiments of the invention, the anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1 (e.g., from the heavy and light chain variable region sequences of BAP049-Clone-E or BAP049-Clone-B disclosed in Table 1) , or encoded by a nucleotide sequence shown in Table 1. In some embodiments, the CDRs are according to the Kabat definition (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 combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 1) . In one embodiment, the combination of Kabat and Chothia CDR of VH CDR1 comprises the 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., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.
In embodiments of the invention, the anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 501, a VHCDR2 amino acid sequence of SEQ ID NO: 502, and a VHCDR3 amino acid sequence of SEQ ID NO: 503; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 510, a VLCDR2 amino acid sequence of SEQ ID NO: 511, and a VLCDR3 amino acid sequence of SEQ ID NO: 512, each disclosed in Table 1.
In embodiments of the invention, the antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 525, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 526; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of 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 disclosed in Table 1.
In embodiments of the invention, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 506. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 520, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 516. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 520.
In embodiments of the invention, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 516.
In embodiments of the invention, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507, or a nucleotide sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 507. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517, or a nucleotide sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 521 or 517. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507 and a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517.
In embodiments of the invention, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 508. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 518. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 518.
In embodiments of the invention, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509, or a nucleotide sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 509. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519, or a nucleotide sequence at least 85%, 90%, 95%, or 99%identical or higher to SEQ ID NO: 523 or 519. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519.
The antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0210769, incorporated by reference in its entirety.
In certain embodiments, a combined inhibition of a checkpoint inhibitor (e.g., an inhibitor of TIM-3 described herein) with a TGF-β inhibitor is further combined with a PD-1 inhibitor and used to treat a cancer (e.g., a myelofibrosis) .
In some embodiments, the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose between about 100 mg to about 600 mg. e.g., about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 600 mg, about 200 mg to about 500 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, about 300 mg to about 600 mg, about 300 mg to about 500 mg, about 300 mg to about 400 mg, about 400 mg to about 600 mg, about 400 mg to about 500 mg, or about 500 mg to about 600 mg. In some embodiments, the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In some embodiments, the PD-1 inhibitor (e.g., spartalizumab) is administered once every four weeks. In some embodiments, (e.g., spartalizumab) is administered once every three weeks. In some embodiments, (e.g., spartalizumab) is administered intravenously. In some embodiments, (e.g., spartalizumab) is administered over a period of about 20 minutes to 40 minutes (e.g., about 30 minutes) .
In some embodiments, the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose between about 300 mg to about 500 mg (e.g., about 400 mg) , intravenously, over a period of about 20 minutes to about 40 minutes (e.g., about 30 minutes) , once every two weeks. In some embodiments, the PD-1 inhibitor (e.g., spartalizumab) is administered at a dose between about 200 mg to about 400 mg (e.g., about 300 mg) , intravenously, over a period of about 20 minutes to about 40 minutes (e.g., about 30 minutes) , once every three weeks.
In some embodiments, the PD-1 inhibitor (e.g., spartalizumab) is administered in combination with a TIM-3 inhibitor (e.g., an anti-TIM3 antibody) and a TGF-β inhibitor (e.g., NIS793) .
Table 1. Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules
In combinations of the invention, each of the therapeutically active agents can be administered separately, simultaneously or sequentially, in any order.
In combinations of the invention, Compound A and/or TNO155 may be administered in an oral dose form.
In another embodiment, there is provided a pharmaceutical composition comprising a pharmaceutical combination of the invention and at least one pharmaceutically acceptable carrier.
Cancers to be treated
Compound A and combinations of the invention may be useful in the treatment of cancer. In particular, Compound A and combinations of the invention may be useful in the treatment of an cancer which is selected from the group consisting of lung cancer (such as lung adenocarcinoma and non-small cell lung cancer) , colorectal cancer (including colorectal adenocarcinoma) , pancreatic cancer (including pancreatic adenocarcinoma) , uterine cancer (including uterine endometrial cancer) , rectal cancer (including rectal adenocarcinoma) and a solid tumor.
The cancer may be at an early, intermediate, late stage or metastatic cancer. In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is a relapsed cancer. In some embodiments, the cancer is a refractory cancer. In some embodiments, the cancer is a recurrent cancer. In some embodiments, the cancer is an unresectable cancer.
The cancer may be at an early, intermediate, late stage or metastatic cancer.
Compound A and combinations of the invention may also be useful in the treatment of solid malignancies characterized by mutations of RAS.
Compound A and combinations of the invention may also be useful in the treatment of solid malignancies characterized by one or more mutations of KRAS, in particular G12C mutations in KRAS.
Thus, as a further embodiment, the present invention provides the use of Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, alone or in combination with a second therapeutic agent which is selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor in therapy. The present invention provides a triple combination consisting of Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor. As a further embodiment, the present invention provides a combination of the invention for use in therapy. In a preferred embodiment, the therapy or the therapy which the medicament is useful for is selected from a disease which may be treated by inhibition of RAS mutant proteins, in particular, KRAS, HRAS or NRAS G12C mutant proteins. In another embodiment, the invention provides a method of treating a disease, which is treated by inhibition of a RAS mutant protein, in particular, a G12C mutant of either KRAS, HRAS or NRAS protein, in a subject in need thereof, wherein the method comprises the administration of a therapeutically effective amount of a compound of the invention, to the subject.
In a more preferred embodiment, the disease is selected from the afore-mentioned list, suitably non-small cell lung cancer, colorectal cancer and pancreatic cancer. In a preferred embodiment, the therapy is for a disease, which may be treated by inhibition of a RAS mutant protein, in particular, a G12C mutant of either KRAS, HRAS or NRAS protein. In a more preferred embodiment, the disease is selected from the afore-mentioned list, suitably non-small cell lung cancer, colorectal cancer and pancreatic cancer, which is characterized by a G12C mutation in either KRAS, HRAS or NRAS.
In another embodiment is method of treating (e.g., one or more of reducing, inhibiting, or delaying progression) a cancer or a tumor in a subject comprising administering to a subject in need thereof a pharmaceutical composition comprising Compound A, or pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent as described herein.
The present invention therefore provides a method of treating (e.g., one or more of reducing, inhibiting, or delaying progression) cancer or tumor in a patient in need thereof, wherein the method comprises administering to the patient in need thereof, a therapeutically active amount of Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, as a single agent or as combination therapy with a therapeutically active amount of one or two therapeutically active agents selected from TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor (e.g., sparatalizumab) , wherein the cancer is lung cancer (including lung adenocarcinoma and non-small cell lung cancer) , colorectal cancer (including colorectal adenocarcinoma) , pancreatic cancer (including pancreatic adenocarcinoma) , uterine cancer (including uterine endometrial cancer) , rectal cancer (including rectal adenocarcinoma) and a solid tumor, optionally wherein the cancer is KRAS-, NRAS-or HRAS-G12C mutant.
In embodiments of the invention, the subject or patient to be treated is selected from:
- a patient suffering from a KRAS G12C mutant solid tumor (e.g. advanced (metastatic or unresectable) KRAS G12C mutant solid tumor) , optionally wherein the patient has received and failed standard of care therapy or is intolerant or ineligible to approved therapies;
- a patient suffering from KRAS G12C mutant NSCLC (e.g., advanced (metastatic or unresectable) KRAS G12C mutant NSCLC) , optionally wherein the patient who has received and failed a platinum-based chemotherapy regimen and an immune checkpoint inhibitor therapy either in combination or in sequence;
- a patient suffering from KRAS G12C mutant CRC (e.g., advanced (metastatic or unresectable) KRAS G12C mutant CRC) , optionally wherein the patient has received and failed standard of care therapy, including a fluropyrimidine-, oxaliplatin-, and /or irinotecan-based chemotherapy.
In a further embodiment, the Compound A, or pharmaceutically acceptable salt thereof, administered to the subject in need thereof is effective to treat the cancer.
In embodiments of the invention, the amounts of Compound A, or pharmaceutically acceptable salt thereof and the second therapeutic agent-and the third therapeutic agent, if present-are administered to the subject in need thereof and are effective to treat the cancer.
In a further embodiment, the second therapeutic agent or third therapeutic agent is TNO155, or a pharmaceutically acceptable salt thereof.
In a further embodiment, the second therapeutic agent or third therapeutic agent is an immunomodulator, such as a PD-1 inhibitor.
In a further embodiment, the PD-1 inhibitor is selected from PDR001, Nivolumab, Pembrolizumab, Pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, or AMP-224.
In a further embodiment, the PD-1 inhibitor is PDR001 (spartazilumab) .
Doses of Compound A when used alone or in combination therapy according to the present invention are designed to be pharmacologically active and result in an anti-tumor response. In embodiments of the invention, Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, is administered at a therapeutically effective dose ranging from 200 to 1600 mg per day, e.g. from 400 to 1600 mg per day. For example, the total daily dose of Compound A may be selected from 200, 300, 400, 600, 800, 1000, 1200 and 1600 mg. The total daily dose of Compound A may be administered continuously, on a QD (once a day) or BID (twice a day) regimen.
Doses of TNO 155 in the combinations of the present invention are designed to be pharmacologically active and have a potential for a synergistic anti-tumor effect while at the same time minimizing the possibility of unacceptable toxicity due to suppressive activities by both agents on MAPK pathway signaling. Thus TNO155 may be administered at a total daily dose ranging from 10 to 80 mg, or from 10 to 60 mg. For example, the total daily dose of TNO155 may be selected from 10, 15, 20, 30, 40, 60 and 80 mg. The total daily dose of TNO155 may be administered continuously, QD (once a day) or BID (twice a day) on QD or BID on a 2 weeks on/1 week off schedule. The total daily dose of TNO155 may be administered continuously, QD (once a day) or BID (twice a day) on QD or BID on continuously (i.e. without a drug holiday) .
In combinations of the invention, Compound A is administered at a dose ranging from 200 to 1600 mg per day (e.g., 200, 300, 400, 600, 800, 1000, 1200 or 1600 mg) and TNO155 is administered at a dose ranging from 10 to 80 mg (0, 15, 20, 30, 40, 60 or 80 mg) , wherein Compound A is administered on a continuous schedule and TNO is administered either on a two week on/one week off schedule or on a continuous schedule.
In combinations of the invention, spartalizumab is administered at a dose of about 300 mg once every 3 weeks, or at a dose of about 400 mg once every 4 weeks. More preferably, spartalizumab is administered at a dose of about 300 mg once every 3 weeks (Q3W) , by injection (e.g., subcutaneously or intravenously) .
In combinations of the invention, Compound A is administered on a continuous schedule at a dose ranging from 200 to 1600 mg per day (e.g., 200, 300, 400, 600, 800, 1000, 1200 or 1600 mg) and spartalizumab is administered at a dose of about 300 mg once every 3 weeks, or at a dose of about 400 mg once every 4 weeks.
In combinations of the invention, Compound A is administered on a continuous schedule at a dose ranging from 200 to 1600 mg per day (e.g., 200, 300, 400, 600, 800, 1000, 1200 or 1600 mg) , TNO155 is administered either on a two week on/one week off schedule or on a continuous schedule at a dose ranging from 10 to 80 mg (0, 15, 20, 30, 40, 60 or 80 mg) , and spartalizumab is administered at a dose of about 300 mg once every 3 weeks or at a dose of about 400 mg once every 4 weeks.
Pharmaceutical Compositions
Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, may be administered either simultaneously with, or before or after, one or more (e.g., one or two) other therapeutic agents. Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more (e.g., one or two) therapeutic agents selected from Compound A, TNO155 and a PD-1 inhibitor, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the present invention provides a pharmaceutical composition comprising a KRAS G12C inhibitor, such as Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and one or more (e.g., one or two) therapeutically active agents selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For purposes of the present invention, unless designated otherwise, solvates and hydrates are generally considered compositions. Preferably, pharmaceutically acceptable carriers are sterile. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories) , or in a liquid form (including without limitation solutions, suspensions or emulsions) . The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of:
a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;
b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;
c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone;
d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and
e) absorbents, colorants, flavors and sweeteners.
In an embodiment, the pharmaceutical compositions are capsules comprising the active ingredient only.
Tablets may be either film coated or enteric coated according to methods known in the art.
Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs, solutions or solid dispersion. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable prepa-rations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
Suitable compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, for-mulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
As used herein, a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
In one embodiment, the invention provides a product comprising Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition characterized by a KRAS, HRAS or NRAS G12C mutation. Products provided as a combined preparation include a composition comprising the compound of the present invention and one or more (e.g., one or two) therapeutically active agents selected from a SHP2 inhibitor such as TNO155, or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor together in the same pharmaceutical composition, or Compound A, or a pharmaceutically acceptable salt, solvate or hydrate, thereof, and the other therapeutic agent (s) in separate form, e.g. in the form of a kit.
In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent (s) . Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above.
In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof; TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor (e.g., spartalizumab) . In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.
In the combination therapies of the invention, the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the present invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the present invention and the other therapeutic agent) ; (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the present invention and the other therapeutic agent. The compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent. The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
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.
In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
Definitions
The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated, where more general terms whereever used may, independently of each other, be replaced by more specific definitions or remain, thus defining more detailed embodiments of the invention:
In particular, where a dosage is mentioned, it is intended to include a range around the specified value of plus or minus 10%, or plus or minus 5%.
As is customary in the art, dosages refer to the amount of the therapeutic agent in its free form. For example, when a dosage of 20 mg of TNO155 is referred to, and TNO155 is used as its succinate salt, the amount of the therapeutic agent used is equivalent to 20 mg of the free form of TNO155.
The term “subject” or “patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer. Examples of subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In an embodiment, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancers.
The term “treating” or “treatment” as used herein comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or partial or complete eradication of a disorder, such as cancer. Within the meaning of the present disclosure, the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
The terms “comprising” and “including” are used herein in their open-ended and non-limiting sense unless otherwise noted.
The terms “a” and “an” and “the” and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
The term “combination therapy” or “in combination with” refers to the administration of two or more therapeutic agents to treat a condition or disorder described in the present disclosure (e.g., cancer) . Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
The combination therapy can provide “synergy” and prove “synergistic” , i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect can be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. Synergistic effect, as used herein, refers to action of two therapeutic agents such as, for example, a compound TNO155 as a SHP2 inhibitor and Compound A, producing an effect, for example, slowing the symptomatic progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L.B., Clin. Pharmacokinet. 6: 429-453 (1981) ) , the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926) ) and the median-effect equation (Chou, T.C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984) ) . Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.
The term “pharmaceutical combination” as used herein refers to either a fixed combination in one dosage unit form, or non-fixed combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
The phrase "therapeutically-effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term "pharmaceutically-acceptable salts" in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts" , J. Pharm. Sci. 66: 1-19) .
The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. The pharmaceutically acceptable salt of TNO155, for example, is succinate.
In the combination of the invention, Compound A, TNO155 and a PD-1 inhibitor, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have one or more atoms replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into TNO155 and a PD-1 inhibitor include isotopes, where possible, of hydrogen, carbon, nitrogen, oxygen, and chlorine, for example,
2H,
3H,
11C,
13C,
14C,
15N,
35S,
36Cl. The invention includes isotopically labeled TNO155 and a PD-1 inhibitor, for example into which radioactive isotopes, such as
3H and
14C, or non-radioactive isotopes, such as
2H and
13C, are present. Isotopically labelled TNO155 and a PD-1 inhibitor are useful in metabolic studies (with
14C) , reaction kinetic studies (with, for example
2H or
3H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagents. Further, substitution with heavier isotopes, particularly deuterium (i.e.,
2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of either Compound A, TNO155 or a PD-1 inhibitor. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in TNO155 or a PD-1 inhibitor is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated deuterium atom) , at least 4000 (60%deuterium incorporation) , at least 4500 (67.5%deuterium incorporation) , at least 5000 (75%deuterium incorporation) , at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at least 6333.3 (95%deuterium incorporation) , at least 6466.7 (97%deuterium incorporation) , at least 6600 (99%deuterium incorporation) , or at least 6633.3 (99.5%deuterium incorporation) .
In Compound A, a methyl group, e.g. on the indazolyl ring, may be deuterated or perdeuterated.
Examples
Example 1: Preparation of 1- {6- [ (4M
) -4- (5-Chloro-6-methyl-1H
-indazol-4-yl) -5-methyl-3- (1- methyl-1H
-indazol-5-yl) -1H
-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one (Compound A)
A synthesis of 1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one (Compound A) is as described below.
Compound A is also known by the name “a (R) -1- (6- (4- (5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptan-2-yl) prop-2-en-1-one” .
General Methods and Conditions:
Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar) .
Abbreviations used are those conventional in the art.
Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using electrospray, chemical and electron impact ionization methods with a range of instruments of the following configurations: Waters Acquity UPLC with Waters SQ detector or Mass spectra were acquired on LCMS systems using ESI method with a range of instruments of the following configurations: Waters Acquity LCMS with PDA detector. [M+H]
+refers to the protonated molecular ion of the chemical species. NMR spectra were run with Bruker Ultrashield
TM400 (400 MHz) , Bruker Ultrashield
TM600 (600 MHz) and Bruker Ascend
TM400 (400 MHz) spectrometers, both with and without tetramethylsilane as an internal standard. Chemical shifts (δ-values) are reported in ppm downfield from tetramethylsilane, spectra splitting pattern are designated as singlet (s) , doublet (d) , triplet (t) , quartet (q) , multiplet, unresolved or more overlapping signals (m) , broad signal (br) . Solvents are given in parentheses. Only signals of protons that are observed and not overlapping with solvent peaks are reported.
Celite: Celite
R (the Celite corporation) = filtering aid based on diatomaceous earth
Phase separator: Biotage –Isolute phase separator – (Part number: 120-1908-F for 70 mL and part
number: 120-1909-J for 150 mL)
X-ray powder diffraction (XRPD) patterns described herein were obtained using a Bruker Advance D8 in reflection geometry. Powder samples were analyzed using a zero background Si flat sample holder. The radiation was Cu Kα
Patterns were measured between 2° and 40° 2theta.
Sample amount: 5-10 mg
Sample holder: zero background Si flat sample holder
XRPD parameters:
Instrumentation
Microwave: All microwave reactions were conducted in a Biotage Initiator, irradiating at 0–400 W from a magnetron at 2.45 GHz with Robot Eight/Robot Sixty processing capacity, unless otherwise stated.
UPLC-MS and MS analytical Methods: Using Waters Acquity UPLC with Waters SQ detector.
UPLC-MS-1: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 x 50 mm; eluent A: H
2O +0.05%HCOOH + 3.75 mM ammonium acetate; eluent B: CH
3CN + 0.04%HCOOH; gradient: 5 to 98%B in 1.40 min then 98%B for 0.40 min; flow rate: 1 mL/min; column temperature: 60℃.
UPLC-MS-3: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50 mm; eluent A: H
2O +4.76%isopropanol + 0.05%HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05%HCOOH; gradient: 1 to 98%B in 1.7 min then 98%B for 0.1 min min; flow rate: 0.6 mL/min; column temperature: 80℃.
UPLC-MS-4: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 100 mm; eluent A: H
2O +4.76%isopropanol + 0.05%HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05%HCOOH; gradient: 1 to 60%B in 8.4 min then 60 to 98%B in 1 min; flow rate: 0.4 mL/min; column temperature: 80℃.
UPLC-MS-6: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50 mm; eluent A: H
2O +0.05%HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05%HCOOH; gradient: 5 to 98%B in 1.7 min then 98%B for 0.1 min; flow rate: 0.6 mL/min; column temperature: 80℃.
Preparative Methods:
Chiral SFC methods:
C-SFC-1: column: Amylose-C NEO 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40℃; back pressure: 120 bar.
C-SFC-3: column: Chiralpak AD-H 5 μm; 100 x 4.6 mm; mobile phase; flow rate: 3 mL/min; column temperature: 40℃; back pressure: 1800 psi.
Abbreviations:
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to prepare the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. Furthermore, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.
The structures of all final products, intermediates and starting materials are confirmed by standard analytical spectroscopic characteristics, e.g., MS, IR, NMR. The absolute stereochemistry of representative examples of the preferred (most active) atropisomers has been determined by analyses of X-ray crystal structures of complexes in which the respective compounds are bound to the KRASG12C mutant. In all other cases where X-ray structures are not available, the stereochemistry has been assigned by analogy, assuming that, for each pair, the atropoisomer exhibiting the highest activity in the covalent competition assay has the same configuration as observed by X-ray crystallography for the representative examples mentioned above. The absolute stereochemistry is assigned according to the Cahn–Ingold–Prelog rule.
Synthesis of Intermediate C1: tert-butyl 6- (3-bromo-4- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate
Step C. 1: tert-butyl 6- (tosyloxy) -2-azaspiro [3.3] heptane-2-carboxylate (
Intermediate C2)
To a solution of tert-butyl 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylate [1147557-97-8] (2.92 kg, 12.94 mmol) in DCM (16.5 L) were added DMAP (316.12 g, 2.59 mol) and TsCl (2.96 kg, 15.52 mol) at 20 ℃-25 ℃. To the reaction mixture was added dropwise Et
3N (2.62 kg, 25.88 mol) at 10 ℃-20 ℃. The reaction mixture was stirred 0.5 h at 5 ℃-15 ℃ and then was stirred 1.5 h at 18 ℃ -28 ℃. After completion of the reaction, the reaction mixture was concentrated under vacuum. To the residue was added NaCl (5%in water, 23 L) followed by extraction with EtOAc (23 L) . The combined aqueous layers were extracted with EtOAc (10 L x 2) . The combined organic layers were washed with NaHCO
3 (3%in water, 10 L x 2) ) and concentrated under vacuum to give the title compound.
1H NMR (400 MHz, DMSO-d
6) δ 7.81 -7.70 (m, 2H) , 7.53 -7.36 (m, 2H) , 4.79 -4.62 (m, 1H) , 3.84 -3.68 (m, 4H) , 2.46 -2.38 (m, 5H) , 2.26 -2.16 (m, 2H) , 1.33 (s, 9H) . UPLC-MS-1: Rt = 1.18 min; MS m/z [M+H]
+; 368.2.
Step C. 2: 3, 5-dibromo-1H-pyrazole
To a solution of 3, 4, 5-tribromo-1H-pyrazole [17635-44-8] (55.0 g, 182.2 mmol) in anhydrous THF (550 mL) was added at -78 ℃ n-BuLi (145.8 mL, 364.5 mmol) dropwise over 20 min maintaining the internal temperature at -78 ℃/-60 ℃. The RM was stirred at this temperature for 45 min. Then the reaction mixture was carefully quenched with MeOH (109 mL) at -78 ℃ and stirred at this temperature for 30 min. The mixture was allowed to reach to 0 ℃ and stirred for 1 h. Then, the mixture was diluted with EtOAc (750 mL) and HCl (0.5 N, 300 mL) was added. The layers were concentrated under vacuum. The crude residue was dissolved in DCM (100 mL) , cooled to -50 ℃ and petroleum ether (400 mL) was added. The precipitated solid was filtered and washed with n-hexane (250 mL x2) and dried under vacuum to give the title compound.
1H NMR (400 MHz, DMSO-d
6) δ13.5 (br s, 1H) , 6.58 (s, 1H) .
Step C. 3: tert-butyl 6- (3, 5-dibromo-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate
To a solution of tert-butyl 6- (tosyloxy) -2-azaspiro [3.3] heptane-2-carboxylate (Intermediate C2) (Step C. 1, 900 g, 2.40 mol) in DMF (10.8 L) was added Cs
2CO
3 (1988 g, 6.10 mol) and 3, 5-dibromo-1H-pyrazole (Step C. 2, 606 g, 2.68 mol) at 15 ℃. The reaction mixture was stirred at 90 ℃ for 16 h. The reaction mixture was poured into ice-water/brine (80 L) and extracted with EtOAc (20 L) . The aqueous layer was re-extracted with EtOAc (10 L x 2) . The combined organic layers were washed with brine (10 L) , dried (Na
2SO
4) , filtered, and concentrated under vacuum. The residue was triturated with dioxane (1.8 L) and dissolved at 60 ℃. To the light yellow solution was slowly added water (2.2 L) , and recrystallization started after addition of 900 mL of water. The resulting suspension was cooled down to 0 ℃, filtered, and washed with cold water. The filtered cake was triturated with n-heptane, filtered, then dried under vacuum at 40 ℃ to give the title compound.
1H NMR (400 MHz, DMSO-d
6) δ 6.66 (s, 1H) , 4.86 -4.82 (m, 1H) , 3.96 -3.85 (m, 4H) , 2.69 -2.62 (m, 4H) , 1.37 (s, 9H) ; UPLC-MS-3: Rt = 1.19 min; MS m/z [M+H]
+; 420.0 /422.0 /424.0.
Step C. 4: tert-butyl 6- (3-bromo-5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate
(Intermediate C3)
To a solution of tert-butyl 6- (3, 5-dibromo-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (Step C. 3, 960 g, 2.3 mol) in THF (9.6 L) was added n-BuLi (1.2 L, 2.5 mol) dropwise at -80 ℃ under an inert atmosphere. The reaction mixture was stirred 10 min at -80 ℃. To the reaction mixture was then added dropwise iodomethane (1633 g, 11.5 mol) at -80 ℃. After stirring for 5 min at -80 ℃, the reaction mixture was allowed to warm up to 18 ℃. The reaction mixture was poured into sat. aq. NH
4Cl solution (4 L) and extracted with DCM (10 L) . The separated aqueous layer was re-extracted with DCM (5 L) and the combined organic layers were concentrated under vacuum. The crude product was dissolved in 1, 4-dioxane (4.8 L) at 60 ℃, then water (8.00 L) was added dropwise slowly. The resulting suspension was cooled to 17 ℃ and stirred for 30 min. The solid was filtered, washed with water, and dried under vacuum to give the title compound.
1H NMR (400 MHz, DMSO-d
6) δ 6.14 (s, 1H) , 4.74 -4.66 (m, 1H) , 3.95 -3.84 (m, 4H) , 2.61 -2.58 (m, 4H) , 2.20 (s, 3H) , 1.37 (s, 9H) ; UPLC-MS-1: Rt = 1.18 min; MS m/z [M+H]
+; 356.1 /358.1.
Step
C. 5: tert-butyl 6- (3-bromo-4-iodo-5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (Intermediate C4)
To a solution of tert-butyl 6- (3-bromo-5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (Intermediate C3) (Step C. 4, 350 g, 0.980 mol) in acetonitrile (3.5 L) was added NIS (332 g, 1.47 mol) at 15 ℃. The reaction mixture was stirred at 40 ℃ for 6 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (3 L) and washed with water (5 L x 2) . The organic layer was washed with Na
2SO
3 (10%in water, 2 L) , with brine (2 L) , was dried (Na
2SO
4) , filtered, and concentrated under vacuum to give the title compound.
1H NMR (400 MHz, DMSO-d
6) δ 4.81 -4.77 (m, 1H) , 3.94 -3.83 (m, 4H) , 2.61 -5.59 (m, 4H) , 2.26 (s, 3H) , 1.37 (s, 9H) ; UPLC-MS-1: Rt = 1.31 min; MS m/z [M+H]
+; 482.0 /484.0.
Step C. 6: tert-butyl 6- (3-bromo-4- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate
(Intermediate C1)
To a stirred suspension of tert-butyl 6- (3-bromo-4-iodo-5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (Intermediate C4) (Step C. 5, 136 g, 282 mmol) and 5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (Intermediate D1, 116 g, 310 mmol) in 1, 4-dioxane (680 mL) was added aqueous K
3PO
4 (2M, 467 mL, 934 mmol) followed by RuPhos (13.1 g, 28.2 mmol) and RuPhos-Pd-G3 (14.1 g, 16.9 mmol) . The reaction mixture was stirred at 80 ℃ for 1 h under inert atmosphere. After completion of the reaction, the reaction mixture was poured into 1M aqueous NaHCO
3 solution (1 L) and extracted with EtOAc (1L x 3) . The combined organic layers were washed with brine (1 L x3) , dried (Na
2SO
4) , filtered, and concentrated under vacuum. The crude residue was purified by normal phase chromatography (eluent: Petroleum ether /EtOAc from 1/0 to 0/1) to give a yellow oil. The oil was dissolved in petroleum ether (1 L) and MTBE (500 mL) , then concentrated in vacuo to give the title compound.
1H NMR (400 MHz, DMSO-d
6) δ 7.81 (s, 1H) , 7.66 (s, 1H) , 5.94 -5.81 (m, 1H) , 4.90 -4.78 (m, 1H) , 3.99 (br s, 2H) , 3.93 -3.84 (m, 3H) , 3.81 -3.70 (m, 1H) , 2.81 -2.64 (m, 4H) , 2.52 (s, 3H) , 2.46 -2.31 (m, 1H) , 2.11 -1.92 (m, 5H) , 1.82 -1.67 (m, 1H) , 1.64-1.52 (m, 2H) , 1.38 (s, 9H) ; UPLC-MS-3: Rt = 1.30 min; MS m/z [M+H]
+; 604.1 /606.1.
Synthesis of Intermediate D1: 5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole
Step D. 1: 1-chloro-2, 5-dimethyl-4-nitrobenzene
To an ice-cooled solution of 2-chloro-1, 4-dimethylbenzene (3.40 kg, 24.2 mol) in AcOH (20.0 L) was added H
2SO
4 (4.74 kg, 48.4. mol, 2.58 L) followed by a dropwise addition (dropping funnel) of a cold solution of HNO
3 (3.41 kg, 36.3 mol, 2.44 L, 67.0%purity) in H
2SO
4 (19.0 kg, 193. mol, 10.3 L) . The reaction mixture was then allowed to stir at 0 -5 ℃ for 0.5 h. The reaction mixture was poured slowly into crushed ice (35.0 L) and the yellow solid precipitated out. The suspension was filtered and the cake was washed with water (5.00 L x 5) to give a yellow solid which was suspended in MTBE (2.00 L) for 1 h, filtered, and dried to give the title compound as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ 7.90 (s, 1H) , 7.34 (s, 1H) , 2.57 (s, 3H) , 2.42 (s, 3H) .
Step
D. 2: 3-bromo-2-chloro-1, 4-dimethyl-5-nitrobenzene
To a cooled solution of 1-chloro-2, 5-dimethyl-4-nitrobenzene (Step D. 1, 2.00 kg, 10.8 mol) in TFA (10.5 L) was slowly added concentrated H
2SO
4 (4.23 kg, 43.1 mol, 2.30 L) and the reaction mixture was stirred at 20 ℃. NBS (1.92 kg, 10.8 mol) was added in small portions and the reaction mixture was heated at 55 ℃ for 2 h. The reaction mixture was cooled to 25 ℃, then poured into crushed ice solution to obtain a pale white precipitate which was filtered through vacuum, washed with cold water and dried under vacuum to give the title compound as a yellow solid which was used without further purification in the next step.
1H NMR (400 MHz, CDCl
3) δ 7.65 (s, 1H) , 2.60 (s, 3H) , 2.49 (s, 3H) .
Step
D. 3: 3-bromo-4-chloro-2, 5-dimethylaniline
To a ice-cooled solution of 3-bromo-2-chloro-1, 4-dimethyl-5-nitrobenzene (Step D. 2, 2.75 kg, 10.4 mol) in THF (27.5 L) was added HCl (4M, 15.6 L) then Zn (2.72 kg, 41.6 mol) in small portions. The reaction mixture was allowed to stir at 25 ℃ for 2 h. The reaction mixture was basified by addition of a sat. aq. NaHCO
3 solution (untill pH = 8) . The mixture was diluted with EtOAc (2.50 L) and stirred vigorously for 10 min and then filtered through a pad of celite. The organic layer was separated and the aqueous layer was re-extracted with EtOAc (3.00 L x 4) . The combined organic layers were washed with brine (10.0 L) , dried (Na
2SO
4) , filtered and concentrated under vacuum to give the title compound as a yellow solid which was used without further purification in the next step.
1H NMR (400 MHz, DMSO-d
6) δ 6.59 (s, 1H) , 5.23 (s, 2H) , 2.22 (s, 3H) , 2.18 (s, 3H) .
Step D. 4: 3-bromo-4-chloro-2, 5-dimethylbenzenediazonium tetrafluoroborate
BF
3. Et
2O (2.00 kg, 14.1 mol, 1.74 L) was dissolved in DCM (20.0 L) and cooled to -5 to -10 ℃ under nitrogen atmosphere. A solution of 3-bromo-4-chloro-2, 5-dimethylaniline (Step D. 3, 2.20 kg, 9.38 mol) in DCM (5.00 L) was added to above reaction mixture and stirred for 0.5 h. Tert-butyl nitrite (1.16 kg, 11.3 mol, 1.34 L) was added dropwise and the reaction mixture was stirred at the same temperature for 1.5 h. TLC (petroleum ether: EtOAc = 5: 1) showed that starting material (R
f= 0.45) was consumed completely. MTBE (3.00 L) was added to the reaction mixture to give a yellow precipitate, which was filtered through vacuum and washed with cold MTBE (1.50 L x 2) to give the title compound as a yellow solid which was used without further purification in the next step.
Step D. 5: 4-bromo-5-chloro-6-methyl-1H-indazole
To 18-Crown-6 ether (744 g, 2.82 mol) in chloroform (20.0 L) was added KOAc (1.29 kg, 13.2 mol) and the reaction mixture was cooled to 20 ℃. Then 3-bromo-4-chloro-2, 5-dimethylbenzenediazonium tetrafluoroborate (Step D. 4, 3.13 kg, 9.39 mol) was added slowly. The reaction mixture was then allowed to stir at 25 ℃ for 5 h. After completion of the reaction, the reaction mixture was poured into ice cold water (10.0 L) , and the aqueous layer was extracted with DCM (5.00 L x 3) . The combined organic layers were washed with a sat. aq. NaHCO
3 solution (5.00 L) , brine (5.00 L) , dried (Na
2SO
4) , filtered and concentrated under vacuum to give the title compound as a yellow solid.
1H NMR (600 MHz, CDCl
3) δ 10.42 (br s, 1H) , 8.04 (s, 1H) , 7.35 (s, 1H) , 2.58 (s, 3H) . UPLC-MS-1: Rt = 1.02 min; MS m/z [M+H]
+; 243 /245 /247.
Step D. 6: 4-bromo-5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole
To a solution of PTSA (89.8 g, 521 mmol) and 4-bromo-5-chloro-6-methyl-1H-indazole (Step D. 5, 1.28 kg, 5.21 mol) in DCM (12.0 L) was added DHP (658 g, 7.82 mol, 715 mL) dropwise at 25 ℃. The mixture was stirred at 25 ℃ for 1 h. After completion the reaction, the reaction mixture was diluted with water (5.00 L) and the organic layer was separated. The aqueous layer was re-extracted with DCM (2.00 L) . The combined organic layers were washed with a sat. aq. NaHCO
3 solution (1.50 L) , brine (1.50 L) , dried over Na
2SO
4, filtered and concentrated under vacuum. The crude residue was purified by normal phase chromatography (eluent: Petroleum ether/EtOAc from 100/1 to 10/1) to give the title compound as a yellow solid.
1H NMR (600 MHz, DMSO-d
6) δ 8.04 (s, 1H) , 7.81 (s, 1H) , 5.88 -5.79 (m, 1H) , 3.92 -3.83 (m, 1H) , 3.80 -3.68 (m, 1H) , 2.53 (s, 3H) , 2.40 -2.32 (m, 1H) , 2.06-1.99 (m, 1H) , 1.99 -1.93 (m, 1H) , 1.77 -1.69 (m, 1H) , 1.60 -1.56 (m, 2H) . UPLC-MS-6: Rt = 1.32 min; MS m/z [M+H]
+; 329.0 /331.0 /333.0
Step D. 7: 5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole
(Intermediate D. 1)
A suspension of 4-bromo-5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (Step D. 6, 450 g, 1.37 mol) , KOAc (401 g, 4.10 mol) and B
2Pin
2 (520 g, 2.05 mol) in 1, 4-dioxane (3.60 L) was degassed with nitrogen for 0.5 h. Pd (dppf) Cl
2. CH
2Cl
2 (55.7 g, 68.3 mmol) was added and the reaction mixture was stirred at 90 ℃ for 6 h. The reaction mixture was filtered through diatomite and the filter cake was washed with EtOAc (1.50 L x 3) . The mixture was concentrated under vacuum to give a black oil which was purified by normal phase chromatography (eluent: Petroleum ether/EtOAc from 100/1 to 10/1) to give the desired product as brown oil. The residue was suspended in petroleum ether (250 mL) for 1 h to obtain a white precipitate. The suspension was filtered, dried under vacuum to give the title compound as a white solid.
1H NMR (400 MHz, CDCl
3) δ 8.17 (d, 1H) , 7.52 (s, 1H) , 5.69-5.66 (m, 1H) , 3.99 -3.96 (m, 1H) , 3.75 –3.70 (m, 1H) , 2.51 (d, 4H) , 2.21 -2.10 (m, 1H) , 2.09 -1.99 (m, 1H) , 1.84 -1.61 (m, 3H) , 1.44 (s, 12H) ; UPLC-MS-6: Rt = 1.29 min; MS m/z [M+H]
+; 377.1 /379.
Synthesis of Compound A
Step 1: Tert-butyl 6- (4- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate In a 500 mL flask, tert-butyl 6- (3-bromo-4- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -5-methyl-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (Intermediate C1, 10 g, 16.5 mmol) , (1-methyl-1H-indazol-5-yl) boronic acid (6.12 g, 33.1 mmol) , RuPhos (1.16 g, 2.48 mmol) and RuPhos-Pd-G3 (1.66 g, 1.98 mmol) were suspended in toluene (165 mL) under argon. K
3PO
4 (2M, 24.8 mL, 49.6 mmol) was added and the reaction mixture was placed in a preheated oil bath (95 ℃) and stirred for 45 min. The reaction mixture was poured into a sat. aq. NH
4Cl solution and was extracted with EtOAc (x3) . The combined organic layers were washed with a sat. aq. NaHCO
3 solution, dried (phase separator) and concentrated under reduced pressure. The crude residue was diluted with THF (50 mL) ,
(15.9 mmol) was added and the mixture swirled for 1 h at 40 ℃. The mixture was filtered, the filtrate was concentrated and the crude residue was purified by normal phase chromatography (eluent: MeOH in CH
2Cl
2 from 0 to 2%) , the purified fractions were again purified by normal phase chromatography (eluent: MeOH in CH
2Cl
2 from 0 to 2%) to give the title compound as a beige foam. UPLC-MS-3: Rt = 1.23 min; MS m/z [M+H]
+; 656.3 /658.3.
Step 2: 5-Chloro-6-methyl-4- (5-methyl-3- (1-methyl-1H-indazol-5-yl) -1- (2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -1H-indazole
TFA (19.4 mL, 251 mmol) was added to a solution of tert-butyl 6- (4- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (Step 1, 7.17 g, 10.0 mmol) in CH
2Cl
2 (33 mL) . The reaction mixture was stirred at RT under nitrogen for 1.5 h. The RM was concentrated under reduced pressure to give the title compound as a trifluoroacetate salt, which was used without purification in the next step. UPLC-MS-3: Rt = 0.74 min; MS m/z [M+H]
+; 472.3 /474.3.
Step 3: 1- (6- (4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptan-2-yl) prop-2-en-1-one
A mixture of acrylic acid (0.69 mL, 10.1 mmol) , propylphosphonic anhydride (50%in EtOAc, 5.94 mL, 7.53 mmol) and DIPEA (21.6 mL, 126 mmol) in CH
2Cl
2 (80 mL) was stirred for 20 min at RT and then added (dropping funnel) to an ice-cooled solution of 5-chloro-6-methyl-4- (5-methyl-3- (1-methyl-1H-indazol-5-yl) -1- (2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -1H-indazole trifluoroacetate (Step 2, 6.30 mmol) in CH
2Cl
2 (40 mL) . The reaction mixture was stirred at RT under nitrogen for 15 min. The RM was poured into a sat. aq. NaHCO
3 solution and extracted with CH
2Cl
2 (x3) . The combined organic layers were dried (phase separator) and concentrated. The crude residue was diluted with THF (60 mL) and LiOH (2N, 15.7 mL, 31.5 mmol) was added. The mixture was stirred at RT for 30 min until disappearance (UPLC) of the side product resulting from the reaction of the acryloyl chloride with the free NH group of the indazole then was poured into a sat. aq. NaHCO
3 solution and extracted with CH
2Cl
2 (3x) . The combined organic layers were dried (phase separator) and concentrated. The crude residue was purified by normal phase chromatography (eluent: MeOH in CH
2Cl
2 from 0 to 5%) to give the title compound. The isomers were separated by chiral SFC (C-SFC-1; mobile phase: CO
2/ [IPA+0.1%Et
3N] : 69/31) to give
Example 1: a (R) -1- (6- (4- (5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptan-2-yl) prop-2-en-1-one as the second eluting peak (white powder) :
1H NMR (600 MHz, DMSO-d
6) δ 13.1 (s, 1H) , 7.89 (s, 1H) , 7.59 (s, 1H) , 7.55 (s, 1H) , 7.42 (m, 2H) , 7.30 (d, 1H) , 6.33 (m, 1H) , 6.12 (m, 1H) , 5.68 (m, 1H) , 4.91 (m, 1H) , 4.40 (s, 1H) , 4.33 (s, 1H) , 4.11 (s, 1H) , 4.04 (s, 1H) , 3.95 (s, 3H) , 2.96-2.86 (m, 2H) , 2.83-2.78 (m, 2H) , 2.49 (s, 3H) , 2.04 (s, 3H) ; UPLC-MS-4: Rt = 4.22 min; MS m/z [M+H]
+526.3 /528.3; C-SFC-3 (mobile phase: CO
2/ [IPA+0.1%Et
3N] : 67/33) : Rt = 2.23 min. The compound of Example 1 is also referred to as “Compound A” .
The atropisomer of Compound A, a (S) -1- (6- (4- (5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl) -2-azaspiro [3.3] heptan-2-yl) prop-2-en-1-one was obtained as the first eluting peak: C-SFC-3 (mobile phase: CO
2/ [IPA+0.1%Et
3N] : 67/33) : Rt = 1.55 min.
Example 2: Synthesis of crystalline forms of Compound A.
Crystalline forms of Compound A such as the ones described below are particularly suitable in the methods and uses of the invention.
Example 2a: Crystalline isopropyl alcohol (IPA) solvate of Compound A and crystalline hydrate (Modification HA) form of Compound A
25 mg of Compound A (obtained from Example 1 above) was added to 0.1 mL of 2-propanol. The resulting clear solution was stirred at 25℃ for 3 days, after which crystalline solid precipitated out. The solid was collected by centrifuge filtration and dried at ambient condition overnight. The wet cake was characterized as crystalline isopropyl (IPA) solvate of Compound A. Drying of the wet cake at ambient condition overnight provided crystalline hydrate (Modification HA) form.
Crystalline hydrate (Modification HA) form of Compound A was analysed by XRPD and the most characteristic peaks are shown in the Table below.
In particular, the most characteristic peaks of the XRPD pattern of the crystalline hydrate (Modification HA) form may be selected from one, two, three or four peaks having an angle of refraction 2θ values (CuKα
) selected from the group consisting of 8.2°, 11.6°, 12.9°and 18.8°.
Crystalline IPA solvate form of Compound A was analysed by XRPD and the most characteristic peaks are shown in the Table below.
In particular, the most characteristic peaks of the XRPD pattern of the crystalline IPA solvate form may be selected from one, two, or three peaks having an angle of refraction 2θ values (CuKα
) selected from the group consisting of 7.5°, 12.5° and 17.6°.
Example 2b: Crystalline ethanol (EtOH) solvate of Compound A and crystalline hydrate (Modification HA) form of Compound A
25 mg of Compound A (obtained from Example 1 above) was added to 0.1 mL of ethanol. The resulting clear solution was stirred at 25℃ for 3 days. Crystalline hydrate (Modification HA) form of Compound A obtained in example 1 was added as seeds to the resulting solution. The resulting suspension was equilibrated for another 1 day, after which a solid precipitated out. The solid was collected by centrifuge filtration and dried at ambient condition overnight. The wet cake was characterized as crystalline ethanol solvate, which after drying at ambient condition overnight, produced crystalline hydrate (Modification HA) .
Alternatively, 3.1 g of Compound A was added to 20mL of ethanol, the resulting clear solution was stirred at 25℃ for 20 mins. Approximately 50 mg crystalline hydrate (Modification HA) (obtained above) was added as seeds, and the resulting mixture was equilibrated at 25℃ for 6 hours. The resulting suspension was filtrated and the wet cake was characterized as crystalline ethanol solvate. The solid was then dried at ambient condition (25℃, 60-70%Relative Humidity) for 3 days, 2.8 g of Compound A hydrate Modification HA was obtained with a yield of 90%.
Crystalline ethanol solvate form of Compound A was analysed by XRPD and the most characteristic peaks are shown in the Table below.
In particular, the most characteristic peaks of the XRPD pattern of the crystalline ethanol solvate form may be selected from one, two, or three or four peaks having an angle of refraction 2θ values (CuKα
) selected from the group consisting of 7.9°, 12.7°, 18.2° and 23.1°.
Example 2c: alternative preparation of crystalline hydrate (Modification HA) preparation
25 mg of Compound A (obtained from Example 1 above) was added to 0.1mL of methanol. The resulting clear solution was stirred at 25℃ for 3 days. Crystalline hydrate (Modification HA) obtained in example 1 was added as seeds to the resulting solution. The resulting suspension was equilibrated for another 1 day, after which a solid precipitated out. The solid was collected by centrifuge filtration and dried at ambient condition overnight. After drying at ambient condition overnight, the wet cake produced crystalline hydrate (Modification HA) .
Example 2d: crystalline propylene glycol solvate preparation and hydrate (Modification HA) preparation
25 mg of Compound A (obtained from Example 1 above) was added to 0.1mL of propylene glycol. The resulting suspension was stirred at 50℃ for 1 week. The solid was collected by centrifuge filtration. The wet cake obtained after filtration was characterized as crystalline propylene glycol solvate. After drying of the cake at ambient condition for 1 week, crystalline hydrate (Modification HA) was obtained.
Crystalline propylene glycol solvate form of Compound A was analysed by XRPD and the most characteristic peaks are shown in the Table below.
In particular, the most characteristic peaks of the XRPD pattern of the crystalline propylene glycol solvate form may be selected from one, two, or three or four peaks having an angle of refraction 2θvalues (CuKα
) selected from the group consisting of 7.3°, 13.2°, 18.0° and 25.5°.
Example 3
In cellular assays, Compound A demonstrated potent and selective target occupancy. Compound A selectively inhibited downstream effector protein recruitment to KRAS G12C, but not to any other RAS wild-type isoform. Compound A inhibited KRAS-driven oncogenic signaling and proliferation specifically in KRAS G12C-mutant cell lines, but not KRAS WT or MEK Q56P mutant cell lines. In nonclinical KRAS G12C mutant xenograft models in mice, PD responses correlated with Compound A exposure in blood. Upon Compound A treatment, free tumor KRAS G12C levels were robustly reduced in a dose-dependent manner and correlated with inhibition of tumor expression of the MAPK pathway target gene, DUSP-6.
Moreover, daily oral Compound A treatment resulted in dose-dependent anti-tumor activity in MIA PaCa-2 and NCI-H2122 xenograft models in mice. In MIA PaCa-2, Compound A produced tumor stasis at 3 mg/kg and tumor regression at 10 mg/kg, 30 mg/kg and 100 mg/kg. In NCI-H2122, Compound A produced weak tumor-growth inhibition at 10 mg/kg, a moderate tumor-growth inhibition at 30 mg/kg and approximately tumor stasis at 100 mg/kg. Likewise, a twice daily oral treatment with Compound A at 50 mg/kg also achieved approximately tumor stasis in NCI-H2122, indicating AUC as the driver for efficacy.
Overall, Compound A was well tolerated in 4-week rat and dog toxicity studies.
Example 4: In vitro combinations of Compound A with TNO155 in KRASG12C-mutated NSCLC cell lines
10 mM stock solutions of the test compounds were dissolved in 100%DMSO, and stored them in small aliquots at -20℃.
10 KRASG12C-mutated non-small-cell lung carcinoma (NSCLC) cell lines: NCI-H2030, NCI-H358, NCI-H1792, HCC-44, NCI-H1373, Calu-1, NCI-H23, LU99, NCI-H2122 and HCC-1171 were from commercially available sources and cultured at 37℃ 5%CO2 in the media conditions recommended by the provider.
The indicated KRAS G12C-mutated human NSCLC cell lines were dispensed into 384-well tissue culture plates. Cells were treated in triplicates with DMSO, a dose range of Compound A (X axis; 2 nM up to 1.6 μM) , a dose range of TNO155 (Y axis; 19 nM up to 4.5 μM) and the pairwise combination of the two agents for 7 consecutive days. After seventy-two hours, the medium was refreshed by supplementing the same volume per well of culture medium containing the corresponding compounds or DMSO. After the seven days treatment period, cell growth was determined using
(Promega) . One plate was counted prior treatment (= Day 1) . The matrices in Figure 1 report the percentage Growth Inhibition (GI) for each treatment as compared to DMSO-treated cells, with darker colors denoting greater cell growth inhibition and/or cell kill. The data was processed using classical synergy models (Loewe, Bliss) . The synergy scores for the Compound A/TNO155 combinations for the following cell lines were as follows. NCI-H2122: 16.7; HCC-1171: 9.7; NCI-H1373: 6.9. Synergy scores above 2 indicate a synergistic level.
Synergistic cell killing occurred in NCI-H2122 and HCC-1171, while synergistic cell growth inhibition was achieved in NCI-1373 and CALU-1. Limited to no synergy was observed in NCI-H23, HCC-44 and LU99 cell lines. (see Figure 1) .
Example 5: Anti-tumor efficacy of Compound A alone and in combination with TNO155 in Lu99 KRASG12C lung carcinoma mouse xenograft models
A heterozygous KRASG12C lung cancer xenograft model, named Lu99, was used in an efficacy study in mice to study the efficacy and tolerability of Compound A, TNO155 used as single agents, and in combination.
Experiments were performed with female nude mice (Charles River Laboratories, Crl: NU (NCr) -Foxn1nu –Homozygous) . The animals were housed in a 12 h light/dark cycle facility and had access to sterilized food and water ad libitum. Animals were allowed to accommodate at least for 7 days.
The Lu99 human cell line originates from a Lung giant cell carcinoma of a 63 year-old male patient [Yamada et al, 1985] . It carries the allele NM_033360.4 (KRAS) : c. 34G>T and consequently a heterozygous KRAS Gly12Cys mutation. Lu99 cells were grown in sterile conditions in a 37℃ incubator with 5%CO2 for two weeks. The cells were kept in RPMI media supplemented with 10%FCS, 2mM L-Glutamin, 1mM sodium pyruvate and 10mM HEPES, and split 1: 6 every 3 days. Cells were tested negative for mycoplasma and murine viruses in 2012 (Radil case number: 8270-2012) . On the day of injection, cells were harvested after 8 passages in total, including passages from the vendor. Cells were resuspended in 50%HBSS and 50%Matrigel at a final concentration of 10.10
6 cells/ml.
An in vivo combination study of Compound A with TNO155 was conducted in the KRAS G12C-mutated Lu99 xenograft model in female nude mice. Mice were injected subcutaneously with Lu99 human NSCLC cells to induce xenograft tumors and randomized into treatment groups when the mean tumor volume reached ~250 mm
3.
Mice were then treated orally at with vehicle, Compound A at 100 mg/kg once daily, TNO155 at 10 mg/kg twice daily, or a combination of Compound A at 100 mg/kg once daily and TNO155 at 10 mg/kg twice daily.
Compound A and TNO155 were each formulated as a suspension in 0.1%Tween 80 (Fisher Scientific AG #BP338-500) and 0.5%Methylcellulose in water. The control group received a solution of 0.1%Tween 80 (Fisher Scientific AG #BP338-500) and 0.5%Methylcellulose in water.
The treatment period was between 9 to 28 days, depending on the groups. Animals treated with vehicle were terminated at day 9 and TNO155 treated animals at day 14 as their tumor volume reached the authorized limit. Animals treated with Compound A or the combination of Compound A and TNO155 were treated for 28 days, and then kept for 5 more days without any treatment.
Tumor growth was monitored regularly post cell inoculation and animals were randomized into treatment groups (n = 6) when TV reached appropriate volume. During the treatment period, xenograft tumor sizes were measured about 2-3 times per week manually with calipers, and the TV was estimated in mm
3 using the formula: Length x Width
2/2.
While a moderate anti-tumor response with single agent TNO155 compared with vehicle group, Compound A treatment led to Lu99 tumor regression for three weeks while treatment was still ongoing. The combination of these two agents significantly improved the sustainability of response and time to relapse seen with Compound A as a single agent, leading to a tumor response similar to Compound A alone, during the three first weeks of treatment. Tumors did not regrow under treatment, unlike what was observed with Compound A alone. Nonetheless, the lung carcinoma growth resumed when treatment was ended. All animals in the study gained body weight throughout the treatment period. All treatment regimens were acceptable, and the blood exposures of both compounds were in similar range when administrated alone or in combination.
Example 6: Anti-tumor efficacy of Compound A alone and in combination with different schedules of TNO155 in Lu99 KRASG12C lung carcinoma mouse xenograft models
An in vivo combination study of Compound A with different schedules of TNO155 was conducted in the KRAS G12C-mutated Lu99 xenograft model in female nude mice. Mice were injected subcutaneously with Lu99 human NSCLC cells to induce xenograft tumors and randomized into treatment groups when the mean tumor volume reached ~200 mm
3. Mice were treated orally with vehicle, Compound A at 100 mg/kg once daily, TNO155 at 10 mg/kg twice daily continuous, or a combination of Compound A at 100 mg/kg once daily and TNO155 at 10 mg/kg twice daily on a continuous or two weeks on one week off schedule. The treatment period was between 14 to 35 days, depending on the groups. Animals treated with vehicle were terminated at day 14. TNO155 and Compound A treated animals were terminated at day 21. Animals treated with the combination of Compound A and TNO155 were treated for 35 days. Tumor volumes were recorded and are represented as mean ± SEM for each group. Anti-tumor response of treatment groups vs. vehicle group was calculated at day 14 as %T/C or %regression. Daily dosing with Compound A at 100 mg/kg induced tumor regression for approximately two weeks, followed by tumor relapse while treatment was still ongoing. TNO155 given continuously at 10 mg/kg twice daily led to slight tumor growth delay compared to the vehicle group. The combination of Compound A with TNO155 significantly improved the sustainability of response and time to relapse seen with Compound A as a single agent. Hereby, the combination effect was the same regardless whether TNO155 was given at a continuous schedule or a two weeks on, one week off schedule.
Example 7
: Anti-tumor efiicacy of Compound A alone and in combination with TNO155 in Lu99
KRASG12C colorectal mouse xenograft models
An in vivo combination study of Compound A with TNO155 was conducted in a panel of KRAS G12C-mutated patient-derived xenograft (PDX) models of human colorectal cancer. Female nude mice were implanted subcutaneously with tumor fragments from each PDX model. Individual mice were assigned to treatment groups for dosing once their tumor volume reached 200-250mm
3. One animal per PDX model was assigned to each treatment arm. Mice were left untreated (control) , or were treated orally with Compound A at 100 mg/kg daily or a combination of Compound A at 100 mg/kg daily and TNO155 at 10 mg/kg twice daily. The end of study per model was defined as minimum of 28 days treatment, or duration for untreated tumor to reach 1500mm
3, or duration for two doublings of untreated tumor, whichever was slower. Tumor volumes were recorded and are represented as %tumor volume change ± SEM for each group. Daily dosing with Compound A led to regression of one PDX model and to a slight to moderate tumor growth delay in some PDX models. The combination of Compound A with TNO155 improved the response in all PDX models, ranging from strong tumor growth inhibition to tumor regression (see Figure 4) .
Example8: Study of Compound A in patients with advanced solid tumors harboring the KRAS
G12C mutation
A study to assess the safety and tolerability of Compound A single agent and Compound A in combination with TNO155, Compound A in combination with spartalizumab, and Compound A in combination with TNO155 and spartalizumab, and to identify the maximum tolerated dose and/or recommended dose and regimen for future studies is carried out. The study is also carried out to evaluate the anti-tumor activity of the study treatments and to evaluate the immunogenicity of spartalizumab when dosed in combination with Compound A and /or TNO155.
The study is conducted in adult patients with advanced solid tumors who harbor the KRAS G12C mutation. In expansion, advanced (metastatic or unresectable) non-small cell lung cancer patients who harbor the KRAS G12C mutation and who are in the second or third line treatment setting will be enrolled. Additional groups of advanced colorectal cancer patients who have the KRAS G12C mutation and who have failed standard of care therapy (i.e. fluropyrimidine-, oxaliplatin-, and /or irinotecan-based chemotherapy) will also be enrolled in the Compound A single agent and Compound A plus TNO155 expansion groups.
Compound A is administered orally (p.o. ) QD or BID continuously on a 21-day cycle. In embodiments of the invention, Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, is administered at a therapeutically effective dose ranging from 200 to 1600 mg per day, e.g. from 400 to 1600 mg per day. For example, the total daily dose of Compound A may be selected from 200, 300, 400, 600, 800, 1000, 1200 and 1600 mg. The total daily dose of Compound A may be administered continuously, on a QD (once a day) or BID (twice a day) regimen.
TNO155 is administered p.o. QD or BID in a 2 week on/1 week off schedule or continuously.
TNO155 may be administered at a total daily dose ranging from 10 to 80 mg, or from 10 to 60 mg. For example, the total daily dose of TNO155 may be selected from 10, 15, 20, 30, 40, 60 and 80 mg. The total daily dose of TNO155 may be administered continuously, QD (once a day) or BID (twice a day) on QD or BID on a 2 weeks on/1 week off schedule. The total daily dose of TNO155 may be administered continuously, QD (once a day) or BID (twice a day) on QD or BID on continuously (i.e. without a drug holiday) .
Spartalizumab is administered intravenously on a 21-day cycle at a dose of about 300 mg once every 3 weeks, or at a dose of about 400 mg once every 4 weeks.
Efficacy of the therapeutic methods of the invention may be determined by methods well known in the art, e.g. determining Best Overall Response (BOR) , Overall Response Rate (ORR) , Duration of Response (DOR) , Disease Control Rate (DCR) , Progression Free Survival, (PFS) and Overall Survival (OS) per RECIST v. 1.1.
It is understood that the Examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.
Claims (24)
- A method of treating a cancer or a tumor in a subject in need thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of 1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one, (Compound A) , or a pharmaceutically acceptable salt, solvate or hydrate thereof, alone or in combination with one additional therapeutically active agent.
- The method according to claim 1, wherein the additional therapeutically active agent is selected from TNO155, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor.
- The method according to claim 1, wherein the additional therapeutically active agent is TNO155, or a pharmaceutically acceptable salt thereof.
- The method according to claim 1, wherein the additional therapeutically active agent is a PD-1 inhibitor (e.g., spartalizumab) .
- The method according to claim 3, wherein the combination of Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and TNO155, or a pharmaceutically acceptable salt thereof is administered with a PD-1 inhibitor.
- The method according to any one of the previous claims wherein the cancer is selected from non-small cell lung cancer, colorectal cancer, pancreatic cancer and a solid tumor.
- The method according to any one of the previous claims, wherein the therapeutic agents in the combination therapy are administered simultaneously, separately or over a period of time.
- The method according to any one of the previous claims, wherein the amount of each therapeutic agent is administered to the subject in need thereofis effective to treat the cancer or tumor.
- The method according to anyone of the preceding claims wherein the PD-1 inhibitor is selected from PDR001, Nivolumab, Pembrolizumab, Pidizilumab, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, or AMP-224.
- The method according to claim 9 wherein the PD-1 inhibitor is PDR001.
- The method according to any one of claims 1 to 10, wherein (3S, 4S) -8- (6-amino-5- ( (2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine, or pharmaceutically acceptable salt thereof, is administered orally at a total daily dose ranging from 10 to 80 mg, or from 10 to 60 mg.
- The method according to claim 11 wherein the dose per day of TNO155 is on a 21 day cycle of 2 weeks on drug followed by 1 week off drug.
- The method according to claim 11 and 12, wherein PDR001 is administered at a dose of about 300 mg once every 3 weeks.
- The method according to claim 11 and 12 wherein PDR001 is administered at a dose of about 400 mg once every 4 weeks.
- The method according to any one of the previous claims wherein Compound A, or a pharmaceutically acceptable salt, solvate or hydrate thereof, is administered at a therapeutically effective dose ranging from 200 to 1600 mg per day, e.g. from 400 to 1600 mg per day.
- The method according to any one of the previous claims, wherein the subject or patient to be treated is selected from:- a patient suffering from aKRAS G12C mutant solid tumor (e.g. advanced (metastatic or unresectable) KRAS G12C mutant solid tumor) , optionally wherein the patient has received and failed standard of care therapy or is intolerant or ineligible to approved therapies;- a patient suffering from KRAS G12C mutant NSCLC (e.g., advanced (metastatic or unresectable) KRAS G12C mutant NSCLC) , optionally wherein the patient who has received and failed a platinum-based chemotherapy regimen and an immune checkpoint inhibitor therapy either in combination or in sequence; and- a patient suffering from KRAS G12C mutant CRC (e.g., advanced (metastatic or unresectable) KRAS G12C mutant CRC) , optionally wherein the patient has received and failed standard of care therapy, including a fluropyrimidine-, oxaliplatin-, and /or irinotecan-based chemotherapy.
- A pharmaceutical combination comprising(i) 1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one, having the structureor a pharmaceutically acceptable salt, solvate or hydrate thereof,and(ii) (3S, 4S) -8- (6-amino-5- ( (2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (TNO155) , having the structure:or a pharmaceutically acceptable salt thereof.
- A pharmaceutical combination comprising:1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one (Compound A) , or a pharmaceutically acceptable salt, solvate or hydrate thereof, and(ii) a PD-1 inhibitor
- A pharmaceutical combination comprising(i) 1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one (Compound A) , or a pharmaceutically acceptable salt, solvate or hydrate thereof,(ii) TNO155, or a pharmaceutically acceptable salt thereof,and(iii) a PD-1 inhibitor.
- A pharmaceutical combination for use according to any one of claims 17, 18 or 19 for use in a method of treating a cancer or a solid tumor according to any one of claims 1 to 16.
- A compound which is 1- {6- [ (4M) -4- (5-Chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl] -2-azaspiro [3.3] heptan-2-yl} prop-2-en-1-one (Compound A) , or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating a cancer or a tumor, optionally wherein the cancer is selected from non-small cell lung cancer, colorectal cancer, pancreatic cancer and a solid tumor
- A compound for use according to claim 20, wherein the compound is administered in combination with one or two additional therapeutically active agents.
- A compound for use according to claim 21, wherein the one or two additional therapeutically active agents is selected from TNO155, or a pharmaceutically acceptable salt thereof, and(iii) a PD1-inhibitor such as spartalizumab.
- A compound for use according to any one of claims 21 to 23 for use in a method of treating a cancer or a solid tumor according to any one of claims 1 to 16.
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PCT/CN2020/138339 WO2022133731A1 (en) | 2020-12-22 | 2020-12-22 | Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor and for the treatment of cancers |
US18/267,735 US20240082218A1 (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor for the treatment of cancers |
BR112023012301A BR112023012301A2 (en) | 2020-12-22 | 2021-12-20 | PHARMACEUTICAL COMBINATIONS COMPRISING A KRAS G12C INHIBITOR AND USES OF A KRAS G12C INHIBITOR FOR THE TREATMENT OF CANCERS |
MX2023007399A MX2023007399A (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor for the treatment of cancers. |
CA3205008A CA3205008A1 (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor for the treatment of cancers |
CN202180086310.8A CN116710094A (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical combination comprising a KRAS G12C inhibitor and use of a KRAS G12C inhibitor for the treatment of cancer |
EP21909342.4A EP4267134A1 (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor for the treatment of cancers |
KR1020237024857A KR20230127256A (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical Combinations Comprising a KRAS G12C Inhibitor and Use of the KRAS G12C Inhibitor for the Treatment of Cancer |
TW110147765A TW202241414A (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor for the treatment of cancers |
JP2023537266A JP2023554471A (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical combinations comprising KRAS G12C inhibitors and use of KRAS G12C inhibitors for the treatment of cancer |
IL303917A IL303917A (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor for the treatment of cancers |
AU2021408129A AU2021408129A1 (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor for the treatment of cancers |
PCT/CN2021/139694 WO2022135346A1 (en) | 2020-12-22 | 2021-12-20 | Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor for the treatment of cancers |
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