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WO2017037220A1 - Traitement de cancer ros1-positif - Google Patents

Traitement de cancer ros1-positif Download PDF

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Publication number
WO2017037220A1
WO2017037220A1 PCT/EP2016/070694 EP2016070694W WO2017037220A1 WO 2017037220 A1 WO2017037220 A1 WO 2017037220A1 EP 2016070694 W EP2016070694 W EP 2016070694W WO 2017037220 A1 WO2017037220 A1 WO 2017037220A1
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WIPO (PCT)
Prior art keywords
ros1
inhibitor
tivozanib
use according
cancer
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Inventor
Harald JANOVJAK
Eva REICHHART
Alvaro INGLES PRIETO
Markus MUELLNER
Sebastian NIJMAN
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Ist Austria
CEMM Forschungszentrum fuer Molekulare Medizin GmbH
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Ist Austria
CEMM Forschungszentrum fuer Molekulare Medizin GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to cancer treatment using a ROS1 inhibitor.
  • Receptor tyrosine kinases are a large family of cell surface receptors that sense growth factors and hormones and regulate a variety of cell behaviors, such as cell proliferation and survival. Unregulated and constitutive RTK activation through chromosomal rearrangements, point mutations, and gene amplification has been shown to be responsible for the initiation and progression of many cancers and other diseases. In turn, defective RTK signaling has been linked to degenerative diseases.
  • the ros oncogene encodes an orphan RTK related to anaplastic lymphoma kinase (ALK), along with members of the insulin-receptor family [1 ].
  • ROS1 c-ROS proto-oncogene 1 receptor tyrosine kinase
  • NSCLC non-small cell lung cancer
  • ROS1 signaling is constitutively activated by interchromosomal translocation or intrachromosomal deletion that results in ROS1 fusion genes.
  • ROS1 kinase domain fusion proteins have been identified, including the Fused in Glioblastoma-ROSI (FIG-ROS), first in a human glioblastoma cell line [6] and later in patients with NSCLC [7], cholangiocarcinoma [8], and serous ovarian carcinoma [9].
  • Fused in Glioblastoma-ROSI Fused in Glioblastoma-ROSI (FIG-ROS)
  • Fused in Glioblastoma-ROSI Fused in Glioblastoma-ROSI (FIG-ROS)
  • SLC34A2-ROS1 (SLC-ROS) fusion is present in a subset of patients with NSCLC [10, 1 1 ] and gastric cancer [12].
  • ROS1 fusions include CD74-ROS1 , EZR- ROS1 , LRIG3-ROS1 , SDC4-ROS1 , TPM3-ROS1 , among others [13].
  • patients with ROS1 rearrangements are significantly younger and more likely to be never-smokers[10] .
  • ROS1 G2032R ROS1 kinase domain mutation
  • ROS1 and ROS1 mutants inhibitors were employed unbiased, high-throughput kinase inhibitor screening assay and discovered that PF-06463922 (originally an ALK inhibitor) [21 , 22], cabozantinib (originally a cMET/RET/VEGFR inhibitor) [23] and foretinib (originally a cMETA/EGFR inhibitor) [24] are potent inhibitors of ROS1 and ROS1 G2032R These drugs selectively suppress receptor activity when tested in cellular-based assays.
  • PF- 06463922 and cabozantinib are currently undergoing phase l/ll clinical trial investigation (ClinicalTrials.gov Id: NCT01970865 and NCT01639508, respectively) against ALK/ROS1 positive NSCLC. Furthermore, cabozantinib is currently clinically available to treat medullary thyroid cancer against cMET, VEGFR2 and RET (ClinicalTrials.gov Id: NCT016831 10). However, none of them has been currently approved for the use in ROS1 -fusion positive tumors. Therefore, there is still an urgent need for the discovery of new agents to target ROS1 fusion-positive cancers, especially for those that are effective against ROS1 mutants.
  • ROS1 positive tumors are malignant epithelial tumors, such as in NSCLC, gastric cancer, serous ovarian carcinoma or cholangiocarcinoma.
  • Rothenstein et al. [25] summarize the management of treatment related adverse events that can arise with ALK inhibitors such as crizotinib and second-generation ALK inhibitors. Although those inhibitors are generally well tolerated, they have a unique side effect profile that differs from that of traditionally cytotoxic therapy and treatment will be often for long periods of time.
  • Katayama et al. [23] describe a model of acquired resistance to ROS1 inhibitors in NSCLC with ROS1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance by high throughput drug screening with small molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials.
  • Tivozanib (AV-951 , KRN951 ) is known as a potent, selective, long half-life inhibitor of all three vascular endothelial growth factor (VEGF) receptors that is designed to optimize VEGF blockade while minimizing off -target toxicities [27]. It has previously been shown that tivozanib has the activity of reversing multidrug resistance mediated by ABCB1 (p-glycoprotein) and ABCG2 transporters (BCRP), two common mechanism of resistance against small molecules [28]. However, data found in online repositories indicate that tivozanib is not efficiently inhibiting ALK.
  • ABCB1 p-glycoprotein
  • BCRP ABCG2 transporters
  • WO2013/158859A1 discloses treatment of NSCLC, which can express ALK and ROS1 in a mutually exclusive way. Crizotinib or TAE-684 inhibiting both, ROS1 activity and ALK activity, is suggested for treating NSCLC.
  • AU2015100 840A4 discloses an oncogenic ROS1 kinase inhibitor that exhibits anti-cancer activity in an NSCLC cell with ROS1 fusion gene.
  • US2014/243332A1 discloses treatment of cancers characterized by aberrant ROS1 activity by administering an effective amount of foretinib.
  • the invention provides for a ROS1 inhibitor for use in the treatment of a subject suffering from ROS1 positive cancer, wherein the inhibitor is tivozanib.
  • tivozanib is dosed at 0.5-2.0 mg daily, preferably at 1 .5 mg daily. Specifically, tivozanib is administered orally one dose per day for three weeks, optionally followed by one week off treatment (i.e., without tivozanib administration).
  • tivozanib is 1 - ⁇ 2-Chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl ⁇ - 3-(5-methylisoxazol-3-yl)urea or 1 - ⁇ 2-Chloro-4-[(6,7-dimethoxyquinolin-4- yl )oxy]phenyl ⁇ -3-(5-methyl isoxazol-3-yl ) urea monohydrochloric acid salt monohydrate.
  • tivozanib is administered in combination with another inhibitor targeting any of ROS , c-MET, VEGF or RET.
  • Said another inhibitor is preferably an antagonist molecule specifically binding to any of ROS1 , c-MET, VEGF or RET, preferably wherein said antagonist molecule is any of a small molecule, polypeptide, peptide, nucleic acid, or oligonucleotide, specifically a chemotherapeutic agent and/or a therapeutic antibody.
  • the chemotherapeutic agent is selected from mitotic inhibitors, alkylating agents, anti-metabolites, proteasome inhibitor, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
  • the therapeutic antibody is specifically recognizing a human target selected from the group consisting of vascular endothelial growth factor (VEGF) or its receptor (VEGFR), epidermal growth factor receptor (EGFR), epidermal growth factor receptor-3 (HER3), PD-1 , hepatocyte growth factor (HGF), insulin-like growth factor-1 receptor (IGF-1 R), and delta-like ligand 4 (DLL4).
  • VEGF vascular endothelial growth factor
  • VEGFR epidermal growth factor receptor
  • HER3 epidermal growth factor receptor-3
  • PD-1 hepatocyte growth factor
  • HGF hepatocyte growth factor
  • IGF-1 R insulin-like growth factor-1 receptor
  • DLL4 delta-like ligand 4
  • tivozanib is used in combination with any of chemotherapy, immunotherapy and/or radiotherapy.
  • tivozanib is used in first-line therapy, or in the therapy of relapsed subjects following chemotherapy, immunotherapy and/or radiotherapy.
  • chemotherapy is employed with a chemotherapeutic agent, such as cisplatin or carboplatin.
  • tivozanib is used adjuvant or neoadjuvant chemotherapy, optionally with further treatment, preferably with surgical resection of the tumor and/or stereotactic body radiotherapy (SBRT).
  • SBRT stereotactic body radiotherapy
  • the ROS1 positivity or the level of ROS1 expression of the cancer is determined in a biological sample containing tumor cells obtained from the subject, preferably by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and quantitative real-time reverse transcription-PCR (qRT-PCR).
  • FISH fluorescence in situ hybridization
  • IHC immunohistochemistry
  • qRT-PCR quantitative real-time reverse transcription-PCR
  • the ROS1 positivity or expression of a tumor cell is determined by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and quantitative real-time reverse transcription-PCR (qRT-PCR).
  • FISH fluorescence in situ hybridization
  • IHC immunohistochemistry
  • qRT-PCR quantitative real-time reverse transcription-PCR
  • the biological sample comprises any of serum, blood, faeces, tissue, a cell, urine or saliva of said human.
  • ROS1 positivity is determined as ROS1 -fusion protein (e.g. by IHC) and/or ROS -fusion gene (e.g. by FISH), and/or ROS1 mRNA (e.g. by qRT-PCR), preferably indicative of a ROS1 -fusion protein selected from the group consisting of SLC34A2-ROS1 (SLC34A2 exons 13del2046 and 4 fused to ROS1 exons 32 and 34, SEQ ID 7 and 8), CD74-ROS1 (CD74 exon 6 fused to ROS1 exons 32 and 34, SEQ ID 9 and 10), EZR-ROS1 (EZR exon 10 fused to ROS1 exon 34 SEQ ID 1 1 ), TPM3-ROS1 (TPM3 exon 8 fused to ROS1 exon 35 SEQ ID 12), LRIG3-ROS1 (LRIG3 exon 16 fused to ROS1 exon 35 SEQ ID 13), SDC4
  • ROS1 positivity is determined by the level and/or activity of ROSI wt and/or ROS1 G2932R mutant.
  • the subject of the present invention refers to treatment of ROS1 rearranged NSCLC.
  • the subject suffers from crizotinib or ceritinib resistance.
  • the subject is a patient with crizotinib-related ROS1 fusion positive tumor that acquired a ROS1 kinase domain mutation (ROS1 G2032R ) that confers crizotinib resistance.
  • ROS1 G2032R ROS1 kinase domain mutation
  • the subject is a human being, more specifically, a human patient.
  • the subject suffers from a malignant epithelial tumor or adenocarcinoma, specifically wherein the tumor cells are ALK/ROS1 positive.
  • the cancer is any of NSCLC, gastric cancer, serous ovarian carcinoma or cholangiocarcinoma.
  • the subject suffers from early or late stage cancer.
  • the patient suffers advanced cancer harboring ROS1 rearrangements that is metastatic or unresectable.
  • the invention further provides for a method for antiproliferative treatment of ROS1 positive cancer, wherein a biological sample of a patient suffering from epithelial cancer and containing tumor cells is analysed whether said tumor cells express ROS1 ; and, if the tumor cells express ROS1 , treating said patient with an effective amount of a ROS1 inhibitor, wherein said ROS1 inhibitor is tivozanib.
  • the invention further provides for a method of treating or managing ROS1 positive cancer in a subject, the method comprising identifying a subject who is diagnosed with epithelial cancer and expresses ROS1 in tumor cells; and administering to the subject a therapeutically effective amount of tivozanib.
  • the invention provides for a method comprising: a) detecting a level of ROS1 expression and/or activity in a tumor cell obtained from a subject diagnosed with epithelial cancer; and
  • the invention provides for a method of treating or preventing tumor proliferation and/or metastasis, comprising:
  • control or control level is obtained from a reference sample, such as a sample obtained from a tumor or a cancer patient diagnosed with a tumor that is ROS1 negative, i.e. a negative control.
  • the higher or elevated level as compared to a control or reference value may be higher than a threshold or cut-off value, or higher than a reference value derived from a comparable sample.
  • Expression may as well be determined by comparison to standards, including internal or external standards.
  • the term shall refer to at least a two-fold higher amount of the standard deviation, preferably at least a three-fold difference.
  • a significant increased amount is understood to refer to an at least 1 .5 fold higher amount, preferably at least 2 or 3 fold difference.
  • the invention provides for a kit for use in the treatment of ROS1 positive cancer, which comprises:
  • kit is provided for the use of tivozanib according to the invention and as further described herein.
  • the kit is provided for use in the treatment of a subject suffering from ROS1 positive cancer, in particular, where the subject suffers from crizotinib resistance.
  • the subject is a patient with crizotinib-reated ROS1 fusion positive tumor that acquired a ROS1 kinase domain mutation (ROS1 G2032R ) that confers crizotinib resistance.
  • HEK293 cells were engineered to contain an Opto-RTK (Opto-mFGFR1 , Opto-hEGFR or Opto-hROS1 ) and a MAPK/ERK pathway-responsive GFP reporter (SRE-GFP).
  • effects of small molecules e.g. receptor inhibitors or pathway inhibitors
  • SRE-GFP MAPK/ERK pathway-responsive GFP reporter
  • effects of small molecules are tested in 384 -well plates by first activating the RTK with blue light ( ⁇ -470 nm, I— 200 pW/cm 2 ) followed by detection of pathway activity using the GFP reporter. For instance, for cells treated with inhibitors of RTKs or of components of the MAPK/ERK pathway, GFP expression will be absent.
  • Transfection can be omitted when a stable cell line is used. ** Drug addition can be performed at the beginning of the workflow by preparing drugs in the 384-well plates. Individual steps and media are described in EXAMPLE 1 , Materials and Methods section.
  • FIG. 4 Light activation of an orphan RTK.
  • the orphan RTK hROS1 was re-engineered to be activated by light by fusing its cytosolic domain (LBD) to the dimerizing LOV domain (LOV). Except for LCD of hROS1 , myristoylation (MYR), transmembrane (TMD), kinase (KD) and C-terminal (CTD) domains are drawn to scale (length of amino acid sequences),
  • MYR myristoylation
  • TMD transmembrane
  • KD kinase
  • Mean raw fluorescence units (RFU) ⁇ SD one representative experiment performed in triplicates) are shown.
  • FIG. 7 Inhibition of Opto-hROS1 G2032R by tivozanib. Control experiments demonstrating activation of MAPK/ERK pathway by Opto-h ROS 1 G2032R and specific inhibition by Tivozanib (T; final concentration 100 nM). Mean raw fluorescence units (RFU) ⁇ SD (one representative experiment performed in triplicates) are shown. Fiqure 8. Inhibition of the hROS1 G2032R -MAPK/ERK-axis (rombs) by increasing doses of tivozanib. Experiments were performed as described in EXAMPLE 2, Materials and Methods section. Mean normalized (to datapoint with the highest intensity in each experiment) fluorescence units (FU) ⁇ SD (one representative experiment) are shown.
  • Figure 9 Inhibition of hROS1 -MAPK/ERK-axis and hROS1 G2032R - MAPK/ERK-axis by tivozanib, crizotinib and PF-06463922. Drug final concentrations are 5 nM (black bars) and 100 nM (striped bars). DMSO (white bars) is shown as a control. Experiments were performed as described in EXAMPLE 2, Materials and Methods section). Mean POC values ⁇ SEM from two independent experiments performed in triplicates are shown.
  • Figure 10 Structural modeling analysis of tivozanib and crizotinib bound to hROS1 and hROS1 G2032R . Comparison of the 3D structures of crizotinib (PDB ID: 3ZBF) and tivozanib (PDB ID: 4ASE) (white spheres) bound to hROS1 (PDB ID: 3ZBF) and modeled hROS1 G2032R . Calculated protein exposed surface is represented in black mesh. hROS1 Gly 2032 (left panels) and hROS1 modeled mutation Arg 2032 (right panels) are represented as black sticks.
  • SEQ ID 7 SLC34A2-ROS1 long transcript (uniprot id: M1 V485)
  • SEQ ID 8 SLC34A2-ROS1 short transcript (uniprot id: A9YLN5)
  • SEQ ID 10 CD74-ROS1 CD74 exon 6 and ROS1 exon 34 (uniprot id: A9YLN4)
  • SEQ ID 1 1 EZR-ROS1 EZR exon 10 and ROS1 exon 34 (uniprot id: J7M2B1 )
  • SEQ ID 12 TMP3-ROS1 TMP3 exon 8 and ROS1 exon 35 (uniprot id: M1 VPF4)
  • SEQ ID 13 LRIG3-ROS1 LRIG3 exon 16 and ROS1 exon 35 (GenBank:
  • SEQ ID 14 SDC4-ROS1 SDC4 exon 4 and ROS1 exon 34 (GenBank: BAM95195.1 )
  • SEQ ID 15 SDC4-ROS1 SDC4 exon 4 and ROS1 exon 32 (GenBank: BAM95194.1 )
  • SEQ ID 16 SDC4-ROS1 SDC4 exon 2 and ROS1 exon 32 (GenBank: BAM95193.1 ) DETAILED DESCRIPTION
  • combination with respect to treatment methods or therapy means coadministering therapeutic agents over a defined time period (e.g., weeks or months), e.g., in a concurrent manner, such as the therapeutic agents can be administered at the same or a different time and can be administered by the same route or by different routes.
  • Combination therapies may employ administration of a therapeutic agent concurrent with surgical interventions and/or radiotherapy, e.g., the medical use o tivozanib as described herein may be combined with standard therapies, e.g. chemotherapy, immunotherapy and/or radiotherapy.
  • Tivozanib in combination with another therapeutic agent may be provided in the same pharmaceutical preparation or in different pharmaceutical preparations, e.g. at the same time or at different times.
  • tivozanib may be provided in combination with said another therapeutic agent in a combination kit. Therefore, the invention further provides for a kit comprising one or more components to be used in combination as described herein in different containers.
  • the kit may include, in addition tivozanib, one or more chemotherapeutic drugs, and optionally various other therapeutic agents and auxiliary agents and devices to prepare pharmaceutical formulations ready for use.
  • a kit may also include instructions for use in a therapeutic method. Such instructions can be, for example, provided on a device included in the kit.
  • the kit includes tivozanib in combination with pharmaceutically acceptable carrier(s) that can be mixed before use to produce an injectable solution for near term administration.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • LCC large cell carcinomas
  • ADC adenocarcinomas
  • SCC squamous cell carcinomas
  • NSCLC can be any of early stage to late stage cancer, e.g. metastatic cancer.
  • the medical use as described herein shall refer to treatment of stages Stage 0 (carcinoma in situ), Stage I, Stage II, Stage IIIA, Stage 1MB, or Stage IV.
  • gastric cancer as used herein synonymously with the term “stomach cancer” shall refer to a disease in which malignant tumor cells form in the lining of the stomach.
  • the majority of gastric cancers are adenocarcinomas. Gastric cancer is often diagnosed at an advanced stage because there are no early signs or symptoms.
  • Surgery to remove the stomach (total gastrectomy) or part (partial gastrectomy) of the stomach is the only treatment known to cure this cancer. Radiation therapy and chemotherapy may be used after the surgery to improve the chance of a cure. In patients who cannot have surgery, radiation and chemotherapy may be used to improve symptoms and prolong survival.
  • serous ovarian carcinoma shall refer to a malignant neoplasm that originates from the ovary (ovarian cancer) or fallopian tube (fallopian tube cancer), and in most cases is serous epithelial cancer started in the epithelial surface layer covering the ovary or fallopian tubes.
  • Serous ovarian carcinomas are graded into low-grade and high-grade.
  • Low-grade serous carcinomas exhibit low-grade nuclei with infrequent mitotic figures. They evolve from adenofibromas or borderline tumors, have frequent mutations of the KRAS, BRAF, or ERBB2 genes, and lack TP53 mutations (Type I pathway).
  • the progression to invasive carcinoma is a slow step-wise process. Low-grade tumors are indolent and have better outcome than high-grade tumors. In contrast, high-grade serous carcinomas have high-grade nuclei and numerous mitotic figures.
  • cholangiocarcinoma as used herein shall refer malignant neoplasm composed of mutated epithelial cells that originate in the bile ducts which drain bile from the Iiver into the small intestine. Most patients have advanced stage disease at presentation and are inoperable at the time of diagnosis. Patients with cholangiocarcinoma are generally managed with chemotherapy, radiation therapy, and other palliative care measures. These are also used as adjuvant therapies (i.e., post- surgically) in cases where resection has apparently been successful.
  • Radiotherapy In ROS1 positive cancer surgery is the most common treatment for resectable tumors, is sometimes followed by chemotherapy.
  • Chemotherapy may be given at the same time as radiotherapy, e.g., as concomitant chemoradiation or concurrent chemoradiation.
  • radiotherapy is used after chemotherapy (sequential treatment), after surgery (adjuvant radiotherapy), or to improve cancer symptoms.
  • Any standard cancer treatment is suitably combined with the tivozanib treatment as decribed herein.
  • ROS1 as used herein shall refer to the receptor tyrosine kinase which is an orphan receptor tyrosine kinase where its ligand is unknown. In the absence of a known natural ligand, ROS1 expression and/or activity of ROS1 is usually determined as follows i) fluorescence in situ hybridization (FISH), which employs a break-aparts probe specific to the ROS1 locus (e.g.
  • FISH fluorescence in situ hybridization
  • ROS1 fusion gene detection kit e.g Amoy Diagnostics Co.
  • ROS1 or human ROS1 (hROS1 ) specifically shall include the ROS1 wild-type (wt) (e.g., human intracellular domain identified by SEQ ID 1 ) and/or ROS1 comprising one or more point mutations, in particular the ROS1 comprising the substitution G2032R, i.e. ROS1 G2032R (e.g., human intracellular domain identified by SEQ ID 2), or other mutations like the gatekeeper mutation L2026 .
  • Some ROS1 mutations were found to confer resistance to ALK inhibitors, such as crizotanib. It has turned out that tivozanib was effectively targeting both ROSI wt and ROS1 G2032R
  • ROS1 specifically shall include the RTK or any oncogenic product thereof including e.g. ROS1 fusion genes and respective ROS1 fusion proteins. ROS1 positivity shall thus specifically include those cases where the level and/or the activity of ROS1 is determined as the level and/or activity of a ROS1 fusion gene or ROS1 fusion protein.
  • ROS1 fusion genes and their expression products that may be determined as a measure of ROS1 fusion genes are e.g., SLC34A2-ROS1 , SDC4-ROS1 , CD74-ROS1 , EZR-ROS1 , TPM3-ROS1 , LRIG3-ROS1 and GOPC- ROS1 .
  • ROS1 fusion proteins and their activities that may be determined as a measure of ROS1 fusion proteins are e.g. SLC34A2-ROS1 , SDC4-ROS1 , CD74- ROS1 , EZR-ROS1 , TPM3-ROS1 , LRIG3-ROS1 and GOPC-ROS1 .
  • inhibitor shall refer to any compound capable of interacting with or binding to a target binding partner under conditions such that the binding partner becomes unresponsive to its natural ligands and/or is rendered inactive upon binding, thereby antagonizing the target.
  • Inhibitors may include, small (organic) molecules, polypeptides (including e.g. proteins), peptides, nucleic acids, or oligonucleotides, in particular chemotherapeutic agents or therapeutic antibodies.
  • the "ROS1 inhibitor” particularly antagonizes with ROS1 constitutive activation and interferes with cell pathways that cause the cancer cells to grow, form new blood vessels, and spread to other organs of the body. The goal of using the ROS1 inhibitor is to shrink the tumour and to prevent it from growing.
  • subject shall refer to a warm-blooded mammalian, including e.g., a human being or a non-human animal, including e.g., dogs, cats, horses, monkeys, rodents (mice and rats), and in particular includes subjects employed in invertebrates animal models (Drosophila melanogaster or Caenorhabditis elegans).
  • the medical use of the invention or the respective method of treatment applies to a subject in need of treatment of a disease which is associated with malignant epithelial tumors identified as being ROS1 positive, or ROS1 positive cancer.
  • the subject may be a patient suffering from disease, including early stage or late stage disease.
  • treating refers to arresting, ameliorating or inhibiting a disease (e.g. the disease, or a related disorder, condition, or symptom), reducing the risk of acquiring a disease, or reducing the development of a disease.
  • a disease e.g. the disease, or a related disorder, condition, or symptom
  • specific treatments are employed in attempts to cure or palliate cancer.
  • management refers to the beneficial effects that a patient derives from a therapy, which does not result in a cure of cancer, but may prevent the progression or worsening of the cancer.
  • terapéuticaally effective amount or “effective amount” as used herein shall refer to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease, provides a therapeutic benefit or is sufficient to affect such treatment of the disease or symptom thereof, e.g., sufficient to delay or minimize the spread of cancer, in particular late stage cancer.
  • effective amount shall particularly refer to amelioration of symptoms associated with malignant epithelial tumors, also encompassing an amount that improves overall therapy, reduces or avoids unwanted effects, or enhances the therapeutic efficacy of or synergizes with one or more antineoplastic agents, utilized in combination therapies as described herein.
  • the therapeutically effective amount may vary depending, e.g., on the compound, the disease and/or symptoms of the disease, severity of the disease and/or symptoms of the disease or disorder, the condition of the patient and the route of delivery. An appropriate amount may be readily ascertained in accordance with routine pharmacological procedures.
  • tivozanib shall refer to the compound also known as AV-951 and KRN951 , with the following formula: 1 - ⁇ 2-Chloro-4-[(6,7- dimethoxyquinolin-4-yl)oxy]phenyl ⁇ -3-(5-methylisoxazol-3-yl)urea and having the chemical structure:
  • tivozanib is or 1 - ⁇ 2-Chloro-4-[(6,7-dimethoxyquinolin-4- yl)oxy]phenyl ⁇ -3-(5-methylisoxazol-3-yl)urea or hydrates of a hydrochloride salt. In certain embodiments, tivozanib is or 1 - ⁇ 2-Chloro-4-[(6,7-dimethoxyquinolin-4- yl)oxy]phenyl ⁇ -3-(5-methylisoxazol-3-yl)urea monohydrochloric acid salt monohydrate.
  • “Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the European Union or U.S. Federal or a state government or listed in the generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • a pharmaceutically acceptable salt is herein understood as a parent compound, which possesses the desired pharmacological activity of the parent compound.
  • Such salts include acid addition salts, formed with inorganic acids and one or more protonable functional groups such as primary, secondary, or tertiary amines within the parent compound.
  • the salts are formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycol ic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fu marie acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane- disulfonic acid.
  • Pharmaceutically acceptable salts may be hydrates or other solvates, as well as salts in crystalline or non-crystalline form.
  • Tivozanib is particularly provided in a pharmaceutical preparation, such as in an oral preparation, e.g., including tablets, capsules, powders, granules, and syrups, or a parental preparation, e.g., including injections (infusion preparations), suppositories, tapes, and ointments.
  • a pharmaceutical preparation such as in an oral preparation, e.g., including tablets, capsules, powders, granules, and syrups, or a parental preparation, e.g., including injections (infusion preparations), suppositories, tapes, and ointments.
  • a pharmaceutical preparation such as in an oral preparation, e.g., including tablets, capsules, powders, granules, and syrups, or a parental preparation, e.g., including injections (infusion preparations), suppositories, tapes, and ointments.
  • These various preparations may be prepared by conventional methods, for example, with commonly
  • Excipients include, for example, lactose, glucose, corn starch, sorbit, and crystalline cellulose; disintegrants include, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, and dextrin; binders include, for example, dimethylcellulose, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, and polyvinyl pyrrolidone; lubricants include, for example, talc, magnesium stearate, polyethylene glycol, and hydrogenated vegetable oils.
  • Liquid formulations can be solutions, emulsions or suspensions and can include excipients such as suspending agents, solubilizers, surfactants, preservatives, and chelating agents.
  • Injections or infusion preparations contain, for example, pharmaceutically acceptable carriers including e.g, sterile water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations of any thereof.
  • Pharmaceutically acceptable carriers suitable used to formulate the pharmaceutical preparation are known in the art and described in, e.g. REMINGTON'S PHARMACEUTICAL SCIENCES.
  • the content of tivozanib in the pharmaceutical composition may vary depending on the dosage form. In general, however, the content is 0.5 to 50% (w/w), preferably 1 to 20% (w/w), based on the whole composition.
  • tivozanib is administered as an oral tablet or capsule or as an intravenous (iv) bolus injection or infusion.
  • iv intravenous
  • the dosage of tivozanib When administered as an oral tablet or capsule, the dosage of tivozanib may be a single capsule or tablet or two or more capsules or tablets.
  • the preparation is typically administered in an amount of 0.01 to 100 mg/kg, preferably 0.1 to 50 mg/kg.
  • This dose can be administered once a day or divided doses of several times daily.
  • a preferred dose is e.g. within the range of 0.5-2.0 mg daily, preferably at 1 .5 mg daily.
  • Tivozanib may be administered on a repeating schedule of one dose per day for one or more weeks, e.g. three weeks, followed by a period where tivozanib is not administered, e.g. one week off.
  • tivozanib was previously not found to effectively inhibit ALK, thus, it was not considered as a potential second-generation ALK inhibitor. Therefore, tivozanib has unexpectedly been identified as a potent inhibitor of ROS1 and in particular ROS1 G2032R . This enables the molecularly targeting therapy against ROS1 positive cancer, without the side effect profile typically expected when using an ALK inhibitor.
  • cellular-based screening approach that allows screening for inhibitors against several RTKs (FGFR and EGFR) and the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), tivozanib was found to be a selective inhibitor of the orphan ROS1 .
  • This screening platform uses light for activation and detection of cell signaling, therefore obviating the need for the addition of reagents, limiting the number of operational steps and providing new experimental strategies to increase specificity and counter variability. Because activating ligands are not required, orphan RTKs, such as ROS1 , could be a target for optogenetics-assisted drug screening given that their catalytic domains can be separated from the ligand-sensing domains [31 , 32].
  • tivozanib is provided as selective ROS1 inhibitor for use as molecularly targeted therapy.
  • drug resistance due to the emergence of a ROS1 mutant eg. ROS1 G2032R
  • tivozanib was found to inhibit both ROS1 and ROS1 G2032R activity using the optogenetics-assisted, cell-based drug screening method [33-35].
  • As tivozanib is safe (it is currently undergoing clinical trial investigation for other indications), it may be advanced as a new therapeutic candidate for treating patients with ROS1 -driven malignancies, such as non-small cell lung cancer, gastric cancer, serous ovarian carcinoma or cholangiocarcinoma.
  • EXAMPLE 1 Light activation of cell signaling permits all-optical small molecule screening
  • High-throughput live-cell screens are intricate elements of systems biology studies and drug discovery pipelines.
  • an optogenetics-assisted method is demonstrated that obviates the addition of chemical activators and reporters, reduces and the number of operational steps in a cell-based small molecule screen against protein kinases including the Orphan' ROS1 receptor tyrosine kinase.
  • This blueprint for all-optical screening can be adapted also to other drug targets and cellular processes.
  • RTKs receptor tyrosine kinases
  • MAPK/ERK mitogen- activated protein kinase/extracellular signal-regulated kinase pathway comprising one G-protein (Ras) and three intracellular kinases (Raf, MEK and ERK). It was demonstrated that in this screening method the use of light for activation and detection of cell signaling obviates the need for the addition of reagents, limits the number of operational steps and provides new experimental strategies to increase specificity and counter variability.
  • the MAPK/ERK pathway is activated by RTKs and regulates cell survival, proliferation and differentiation. Modulators of the MAPK/ERK pathway, of RTKs and of other protein kinases are intensively pursued as new therapeutics in cancer and metabolic and neurodegenerative disorders.
  • First human embryonic kidney 293 (HEK293) cells were engineered that contain light-activated RTKs and a genetic fluorescent MAPK/ERK pathway reporter (Fig. 1a).
  • the light-activated RTKs also called Opto-RTKs'
  • LUV light-oxygen-voltage-sensing
  • Opto-RTKs the light-activated murine fibroblast growth factor receptor 1 (Opto-mFGFR1 ) and the light-activated human epidermal growth factor receptor (Opto-hEGFR), were initially employed to set-up this platform.
  • Opto-mFGFR1 the light-activated murine fibroblast growth factor receptor 1
  • Opto-hEGFR the light-activated human epidermal growth factor receptor
  • the engineered cells respond to light stimulation at a wavelength and intensity suited for Opto-RTK activation ( ⁇ 470 nm, intensity-200 pW/cm 2 ) with increased production of GFP (Fig. 1 b), and the combination of Opto- RTKs and the GFP reporter thus enables a novel 'all-optical' mode of operation where light is used to activate as well as to read cellular signaling.
  • This method functions without added reagents (e.g. peptide ligands or detection assays) and a reduced number of operational steps as the method does not require physical contact to the living cells. Furthermore, because activation by a peptide or other agonist is not required, the all-optical method has the capability to conduct screens against 'orphan' receptors, i.e. receptors for which native ligands are not known. To demonstrate the optical control of an orphan receptor, a de novo database search and bioinformatics analysis was first conducted to identify human orphan RTKs (Fig. 3 and Materials and Methods).
  • hROS1 human ROS1
  • Opto-hROS1 the dimerizing LOV domain was fused to the intracellular domain of hROS1 (Fig. 4 and Materials and Methods).
  • Fig. 5 three molecules that inhibited the hROS1 -MAPK/ERK-axis were found (Fig. 5).
  • crizotinib and GSK-1 120212 were known kinase inhibitors of hROS1 and components of the MAPK/ERK pathway, resp.
  • the third molecule (AV-951 ) was active against hROS1 but not hEGFR or mFGFRI (Fig. 6). Notably, AV-951 was previously not assigned to inhibit hROS1 [46].
  • EGF or FGF2 will have bound to several receptor proteins that are expressed in this cell type (FGFR1 , FGFR2, FGFR3, FGFR-like 1 and EGFR), while Opto-RTK activation was specific to the receptor that was engineered.
  • Activation by light in real time may also reveal more detailed insights into molecular inhibition and cellular signaling mechanisms. For instance, the interaction between small molecules and proteins may be activation-state dependent [47, 48], and the duration and frequency of activation may determine the choice of pathway or functional outcome [49, 50].
  • the ability to switch signals on with temporal precision and tunable strength, even within the same well, may be used to explore these phenomena in a systematic and automated manner.
  • Small molecules are listed in Table 1 . Out of the tested 68 small molecules, 62 molecules target protein kinases.
  • Opto-mFGFR1 and Opto-hEGFR in pcDNA3.1 (-) were described previously [43]. Identification of hROS1 and genetic engineering of Opto- hROS1 is described below.
  • the SRE-GFP reporter vector was obtained from Qiagen/SA Biosciences.
  • HEK293 were derived by F.L. Graham (McMaster University). HEK293 cells were maintained in DMEM, resp., in a humidified incubator with 5% CO2 atmosphere. Media was supplemented with 10% FBS, 100 U/ml penicillin and 0.1 mg/ml streptomycin.
  • FBS penicillin
  • streptomycin 100 U/ml penicillin
  • streptomycin 100 U/ml penicillin
  • streptomycin 100 U/ml
  • 2x10 6 cells were seeded in 60 mm cell culture dishes coated with poly-L-ornithine (PLO, Sigma). Cells were transfected with 4.04 to 8.04 pg total DNA per dish (receptor, pcDNA3.1 (-) empty vector, and reporter at a ratio of 1 :50:50 or 1 :100:100) using polyethylenimine (Polysciences).
  • PLO poly-L-ornithine
  • thermoelectric incubator (PT2499, ExoTerra) was equipped with 300 RGB LEDs (5050SMD, X ma x * 630 nm (red light), X max * 530 nm (green light), X max ⁇ 470 nm (blue light), bandwidth 3 ⁇ 4 ⁇ 5 nm).
  • Light intensity was controlled with a dimmer and measured with a digital power meter (PM120VA, Thorlabs). Blue light intensity at maximal output was 247 iiW/cm 2 . Light of this intensity is sufficient for activation and well tolerated by mammalian cells without signs of toxicity even for extended periods of time.
  • HEK293 cells were kept in DMEM (supplemented with 5% FBS and no antibiotics; "D5-AB” medium) for 6 h. Afterwards, 5 ⁇ 00 to 20 ⁇ 00 cells were seeded in each well of 384-well plates (3712, Corning) in low-fluorescence medium (FlouroBrite TM , Life Technologies, supplemented with 25 mM HEPES, 0.5% FBS, 100 U/ml penicillin and 0.1 mg/ml streptomycin, pH 7.5; "COI” medium). Small molecules were added and after 1 h cells were stimulated with blue light in a custom incubator (see above).
  • Orphan RTKs were identified using the bioinformatics procedure described in Fig. 3. Protein family search with the PFAM motif "Pkinase_Tyr" (PF07714) at the Wellcome Trust Sanger Institute (http://pfam.xfam.org/)[51 ] retrieved a comprehensive list of human Tyr kinases.
  • This PFAM motif is a good representative of kinase domains found in RTKs (it was confirmed that it is found in members of diverse RTK families, such as fibroblast growth factor receptors, ErbB receptors, Insulin-like growth factor receptor, neurotrophin receptors, ROR receptors).
  • a sequence coding for the ROS1 gene was obtained from the Mammalian Gene
  • an expression vector was prepared starting from an Opto-mFGFR1 vector in which the mFGFRI ICD was replaced by two inverted Sapl restriction sites.
  • the ROS1 ICD was amplified with oligonucleotides (F: GAT CGC TCT TCA GAG CAT AGA AGA TTA AAG AAT CAA AAA AG (SEQ ID 3), R: GAT CGC TCT TCC AGG ATC AGA CCC ATC TCC ATA TCC ACT G (SEQ ID 4)) and PGR and inserted into the vector using 'Golden Gate' cloning [54].
  • DMSO treated samples, resp., and std (c_) and avg ⁇ c_) are the standard deviation and the average of PD-166866 (INH; final concentration 20 ⁇ ) treated samples, resp.
  • c_ std
  • avg ⁇ c_ std
  • X t is the measurement of the i th small molecule and avg(c + ) is the average measurement of the DMSO treated samples.
  • Table 1 Small molecules used in this example. Number corresponding to compounds in Fig. 1 c and Fig. 5.
  • Table 2 Seed sequences retrieved using the bioinformatics procedure described in Fig. 3. Where necessary for clarity, gene short names were added in square brackets to the Uniprot description. Stars (*) denote RTKs identified as orphans.
  • A8K2T7 Highly similar to Homo sapiens epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog avian) (EGFR)
  • A8KAM8 Highly similar to Homo sapiens platelet-derived growth factor receptor betapolypeptide
  • EXAMPLE 2 Tivozanib is a potent inhibitor against a crizotinib-resistant human ROS1 mutant.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • tivozanib was compared to other known hROS1 and/or hROS1 G2032R inhibitors, such as crizotinib and PF-06463922 (Table 4) at two different concentrations (5nM and 100nM). Using an optogenetics-assisted platform, tivozanib was found to block hROS1 and hROS1 G2032R activity more efficiently than crizotinib and PF-06463922 (Fig. 9), respectively.
  • crizotinib and tivozanib atomic interactions with ROS1 and ROS1 G2032R were compared through structural modeling analysis.
  • both drugs can access easily to the drug binding pocket (Fig. 10), therefore inhibiting the receptor.
  • the mutated Arginine is acting as a "gate-keeper" mutation, impeding the access of crizotinib to the binding pocket (Fig 10); while in case of tivozanib, the flat shape of the molecule can overcome this restriction and enter into the cavity.
  • this result indicates that flatter side-groups are able to lay under "gate-keepers" residues, and therefore this strategy could be use to engineer new kinase inhibitors.
  • tivozanib offers i) longer half-life ( ⁇ 5 days), ii) a lower mean plasma concentration (-1 14 ng/ml), but enough to inhibit both ROS1 and ROS1 G2032 (IC50: 10 and 50 nM, resp.); iii) lower clearance (-0.60 L/h), which enables to reduce the dosage, therefore enhancing the availability and prolonging the half-life of the small molecule; iv) reduced dose in humans (1 .5 mg), which reduces side effects and increase compliance for the patient and v) lower discontinuation percentage (37%).
  • tivozanib is provided as a selective ROS1 and ROS1 G2032R inhibitor for use as molecularly targeted therapy.
  • the structural modeling analysis provided molecular basis of the drug interaction with both targets, which explained the higher inhibition potency.
  • tivozanib is safe in humans and has superior pharmacokinetics and toxicity properties compared to crizotinib. Therefore, tivozanib may be advanced as a new therapeutic candidate for treating patients suffering ROS1 - driven non-small cell lung cancer and other tumors in which ROS1 plays an important role, such as gastric cancer, serous ovarian carcinoma or cholangiocarcinoma.
  • Glycine 2032 in Opto-hROS1 was mutated to Arginine by site directed mutagenesis using oligonucleotides (AAT AAG TAA GAA GGT CTC TTC CCT CCA TCA GTT CCA G (SEQ ID 5) and CTG GAA CTG ATG GAG GGA AGA GAC CTT CTT ACT TAT T (SEQ ID 6)). Mutation was checked by DNA sequencing.
  • HEK293 cells were maintained in DMEM, in a humidified incubator with 5% CO2 atmosphere. Media was supplemented with 10% FBS, 100 U/ml penicillin and 0.1 mg/ml streptomycin.
  • FBS fetal bovine serum
  • streptomycin 100 U/ml penicillin and 0.1 mg/ml streptomycin.
  • 2x10 6 cells were seeded in 60 mm cell culture dishes coated with poly-L-ornithine (PLO, Sigma). Cells were transfected with 4.04 to 8.04 g total DNA per dish (receptor, pcDNA3.1 (-) empty vector, and reporter at a ratio of 1 :50:50 or 1 :100:100) using polyethylenimine (Polysciences).
  • Table 5 Pharmacokinetic and toxicity properties for tivozanib and crizotinib.
  • Davare, M.A., et al., Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proc Natl Acad Sci U S A, 2013. 110(48): p. 19519-24.
  • KRN951 vascular endothelial growth factor receptor tyrosine kinases

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Abstract

L'invention concerne un inhibiteur ROS1 destiné à être utilisé dans le traitement d'un sujet atteint d'un cancer ROS1-positif, l'inhibiteur étant le tivozanib.
PCT/EP2016/070694 2015-09-03 2016-09-02 Traitement de cancer ros1-positif Ceased WO2017037220A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2019107671A1 (fr) * 2017-11-29 2019-06-06 서울대학교 산학협력단 Anticorps anti-ros1 et son utilisation
WO2023096651A1 (fr) * 2021-11-26 2023-06-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Méthodes de traitement des cancers du conduit biliaire avec du tivozanib

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013158859A1 (fr) * 2012-04-18 2013-10-24 Cell Signaling Technology, Inc. Egfr et ros1 dans les cancers
US20140243332A1 (en) * 2013-02-27 2014-08-28 Oregon Health & Science University Methods of treating cancers characterized by aberrent ros1 activity
AU2015100840A4 (en) * 2015-06-19 2015-07-30 Macau University Of Science And Technology Oncogenic ros1 kinase inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013158859A1 (fr) * 2012-04-18 2013-10-24 Cell Signaling Technology, Inc. Egfr et ros1 dans les cancers
US20140243332A1 (en) * 2013-02-27 2014-08-28 Oregon Health & Science University Methods of treating cancers characterized by aberrent ros1 activity
AU2015100840A4 (en) * 2015-06-19 2015-07-30 Macau University Of Science And Technology Oncogenic ros1 kinase inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JAMIL MUHAMMAD OMER ET AL: "Tivozanib: Status of Development", CURRENT ONCOLOGY REPORTS, CURRENT SCIENCE, GB, vol. 17, no. 6, 21 April 2015 (2015-04-21), pages 1 - 7, XP035490123, ISSN: 1523-3790, [retrieved on 20150421], DOI: 10.1007/S11912-015-0451-3 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019107671A1 (fr) * 2017-11-29 2019-06-06 서울대학교 산학협력단 Anticorps anti-ros1 et son utilisation
US12077599B2 (en) 2017-11-29 2024-09-03 Seoul National University R&Db Foundation, National Cancer Center Anti-ROS1 antibody and use thereof
WO2023096651A1 (fr) * 2021-11-26 2023-06-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Méthodes de traitement des cancers du conduit biliaire avec du tivozanib

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