Oncological combination therapy and its use

Abstract

This disclosure provides a method for treating cancer by co-administering prinabulin and a PARP inhibitor (such as talazoparib). Some embodiments of this disclosure relate to compositions comprising prinabulin and a PARP inhibitor (such as talazoparib). Some embodiments also relate to a method for treating cancer by co-administering prinabulin and one or more PARP inhibitors.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 451517, filed on 10 March 2023, the entirety of which is incorporated herein by reference.

[0002] This disclosure relates to the fields of chemistry and medicine, and more specifically, to combination therapies for the treatment of cancer. [Background technology]

[0003] The poly(ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including transcription regulation, apoptosis, and DNA damage response. (Rose et al., Front. Cell Dev. Biol., 8 (2020)(https: / / doi.org / 10.3389 / fcell.2020.564601)). PARP1 has poly(ADP-ribose) activity and, when activated by DNA damage, adds a branched PAR chain to promote the recruitment of other repair proteins and facilitate the repair of single-strand breaks in DNA. PARP inhibitors were the first approved anticancer drugs to specifically target the DNA damage response in breast and ovarian cancers with BRCA1 / 2 mutations. Multiple approvals or clinical trials exist for the use of PARP inhibitors in the anticancer therapy of ovarian, breast, lung, pancreatic, fallopian tube, primary peritoneal, and prostate cancers.

[0004] Despite the success of PARP inhibitor therapy, treatment resistance is universally observed in clinical practice. More than 40% of BRCA1 / 2 deficiency patients do not respond to PARP inhibitor therapy. (Li et al., Molecular Cancer, 19(107) (2020)(https: / / doi.org / 10.1186 / s12943-020-01227-0)). Therefore, improved anticancer therapies utilizing this treatment method are needed. [Overview of the project]

[0005] Some embodiments of this disclosure include a method for treating cancer, comprising co-administering prinabulin and a PARP inhibitor to a subject. In some embodiments, prinabulin is administered intravenously. In some embodiments, the PARP inhibitor is administered orally. In some embodiments, the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, olaparib, rucaparib, veliparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397. In some embodiments, the PARP inhibitor is talazoparib. In some embodiments, talazoparib is administered in doses of 0.25 mg to 5 mg. In some embodiments, talazoparib is administered once daily. In some embodiments, talazoparib is administered twice daily. In some embodiments, the dose of prinabulin administered is 10 mg / m². 2 ~40mg / m 2 In some embodiments, the dose of prinabulin administered is 15 mg to 120 mg. In some embodiments, the dose of prinabulin administered is approximately 40 mg. In some embodiments, prinabulin is administered once a week. In some embodiments, prinabulin is administered twice a week. In some embodiments, prinabulin is administered once every three weeks.

[0006] Some embodiments of this disclosure include pharmaceutical compositions comprising prinabulin or a pharmaceutically acceptable salt thereof and a PARP inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is talazoparib, niraparib, olaparib, or lucaparib. , selected from the group consisting of veliparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397. In some embodiments, the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, rucaparib, veliparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397. In some embodiments, the PARP inhibitor is talazoparib.

[0007] Some embodiments of the present disclosure include a kit comprising a first pharmaceutical composition comprising purinablin or a pharmaceutically acceptable salt thereof and a second pharmaceutical composition comprising a PARP inhibitor.

[0008] In some embodiments, the first pharmaceutical composition is an intravenous administration formulation and the second pharmaceutical composition is an oral formulation.

Brief Description of the Drawings

[0009] [Figure 1] A graph showing the average tumor volume when vehicle control, talazoparib alone, purinablin alone, and the combination of purinablin and talazoparib were administered in a MDA-MB-231 human breast cancer xenograft model. [[ID=I7]]

[0010] [Figure 2] A bar graph showing the total tumor wet weight at death when vehicle control, talazoparib alone, purinablin alone, and the combination of purinablin and talazoparib were administered in a MDA-MB-231 human breast cancer xenograft model.

[0011] [Figure 3] A graph showing the animal survival rate when vehicle control, talazoparib alone, purinablin alone, and the combination of purinablin and talazoparib were administered in a MDA-MB-231 human breast cancer xenograft model.

[0012] [Figure 4] This graph shows the effects of different treatments on weight change over time. [Modes for carrying out the invention]

[0013] This disclosure discloses methods for treating cancer. In some embodiments, the method involves the combined administration of prinabulin and a poly(ADP-ribose) polymerase (PARP) inhibitor. Administration of prinabulin in this disclosure includes the administration of a pharmaceutically acceptable salt or solvate (including a hydrate) of prinabulin. In some embodiments, prinabulin is provided as a monohydrate. Administration of a PARP inhibitor in this disclosure includes the administration of a pharmaceutically acceptable salt of the PARP inhibitor.

[0014] As used in this disclosure, the terms “pharmaceutically acceptable salt” and “that pharmaceutically acceptable salt” are broad terms and should be interpreted in the ordinary and customary sense to those skilled in the art (not limited to any special or customized meanings) and refer without limitation to salts prepared from pharmaceutically acceptable non-toxic acids or bases. Suitable pharmaceutically acceptable salts include metal salts, e.g., salts of aluminum and zinc; alkali metal salts (e.g., lithium, sodium, potassium salts); alkaline earth metal salts (e.g., calcium, magnesium salts); organic salts, e.g., salts of lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and tris; salts of free acids and bases; inorganic salts, e.g., sulfates, hydrochlorides, and hydrobroms; and salts currently widely used as pharmaceuticals and well known to those skilled in the art, such as those found in The Merck Index. Other salts listed in the source may be included. Any suitable component can be selected to form the therapeutic salts discussed herein, provided that it is nontoxic and does not substantially interfere with the desired activity.

[0015] As used in this disclosure, the terms “combined administration” or “combined administration” refer to two or more drugs or therapies that simultaneously exert a biological effect on a subject, regardless of when and how they are actually administered. In one embodiment, the drugs or therapies are administered simultaneously. In such one embodiment, combined administration is achieved by combining the drugs into a single dosage form. In another embodiment, the drugs or therapies are administered sequentially. In some embodiments, the administrations may be spaced apart by periods such as 30 minutes, 1 hour, 2 hours, 1 day, 2 days, 3 days, or 1 week. In one embodiment, the drugs are administered via the same route, such as orally. In another embodiment, the drugs are administered via different routes, for example, one orally and the other intravenously. Prinabrin

[0016] Prinabulin, (3Z,6Z)-3-benzylidene-6-{[5-(2-methyl-2-propanyl)-1H-imidazole-4-yl]methylene}-2,5-piperazinedione, is a synthetic analog of the natural compound phenylahistine. Prinabulin can be readily prepared by the methods and procedures detailed in U.S. Patents 7,064,201 and 7,919,497, which are incorporated in their entirety by reference in this disclosure.

[0017] In some embodiments, the amount of prinabulin is approximately 1 to 50 mg / m² of body surface area. 2 It is administered in doses within the range of [amount]. In some embodiments, prinabulin is approximately 5 to approximately 50 mg / m² of body surface area. 2 It is administered in doses within the range of [amount]. In some embodiments, prinabulin is approximately 20 to 40 mg / m² of body surface area. 2 It is administered in doses within the range of [amount]. In some embodiments, prinabulin is approximately 15 to 30 mg / m² of body surface area. 2Prinabulin is administered in doses within the range of 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-1 per body surface area. 0, 1-11, 1-12, 1-13, 1-13.75, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-22.5, 1-25, 1-27.5, 1-30, 1.5-2, 1.5-3, 1.5-4, 1.5-5, 1.5-6, 1.5-7, 1.5-8, 1.5-9, 1.5-10, 1.5-11, 1.5-12, 1.5-13, 1.5-13.75, 1.5-14, 1.5-15, 1.5-16, 1.5-17, 1.5-18, 1.5-19, 1.5-20, 1.5-22.5, 1.5-25, 1.5-2 7.5, 1.5~30, 2.5~2, 2.5~3, 2.5~4, 2.5~5, 2.5~6, 2.5~7, 2.5~8, 2.5~9, 2.5~10, 2.5~11, 2.5~12, 2.5~13, 2.5~13.75, 2.5~14, 2.5~15, 2.5~16, 2.5~17, 2.5~18, 2.5~19, 2.5~20, 2.5~22.5, 2.5~25, 2.5~27.5, 2.5~30, 2.5~7.5, 3~4, 3~5, 3~6, ​​3~7, 3~8, 3~9, 3~10, 3~11, 3~12, 3~13, 3~13.75, 3 ~14, 3~15, 3~16, 3~17, 3~18, 3~19, 3~20, 3~22.5, 3~25, 3~27.5, 3~30, 3.5~6.5, 3.5~13.75, 3.5~15, 2.5~17.5, 4~5, 4~6, 4~7, 4~8, 4~9, 4~10, 4~11, 4~12, 4~13, 4~13.75, 4~14, 4~15, 4~16, 4~17, 4~18, 4~19, 4~20, 4~22.5, 4~25, 4~27.5, 4~30, 5~6, 5~7, 5~8, 5~9, 5~10, 5~11, 5~12, 5~13, 5~13.75, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-22.5, 5-25, 5-27.5, 5-30, 6-7, 6-8, 6-. 9, 6~10, 6~11, 6~12, 6~13, 6~13.75, 6~14, 6~15, 6~16, 6~17, 6~18, 6~19, 6~20, 6~22.5, 6~25, 6~27.5, 6~30, 7~8, 7~9, 7~10, 7~11, 7~12, 7~13, 7~13.75, 7~14, 7~15, 7~16, 7~17, 7~18, 7 ~19, 7~20, 7~22.5, 7~25, 7~27.5, 7~30, 7.5~12.5, 7.5~13.5, 7.5~15, 8~9, 8~10, 8~11, 8~12, 8~13, 8~13.75, 8~14, 8~15, 8~16, 8~17, 8~18, 8~19, 8~20, 8~22.5, 8~25, 8~27.5, 8~30, 9~ 10, 9~11, 9~12, 9~13, 9~13.75, 9~14, 9~15, 9~16, 9~17, 9~18, 9~19, 9~20, 9~22.5, 9~25, 9~27.5, 9~30, 10~11, 10~12, 10~13, 10~13.75, 10~14, 10~15, 10~16, 10~17, 10~18, 10~19, 10~ 20, 10-22.5, 10-25, 10-27.5, 10-30, 10-40, 11.5-15.5, 12.5-14.5, 7.5-22.5, 8.5-32.5, 9.5-15.5, 15.5-24.5, 5-35, 17.5-22.5, 22.5-32.5, 25-35, 25.5-24.5, 27.5-32.5, 2-20, t 2.5-22.5, or 9.5-21.5 mg / m² 2It is administered at a dosage within the range. In some embodiments, purinabulin is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / m 2 It is administered at a dosage. In some embodiments, purinabulin is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40mg / m 2 It is administered at a dosage less than. In some embodiments, purinabulin is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50mg / m 2It is administered in doses exceeding [a certain amount]. In some embodiments, prinabulin is approximately 10, 13.5, 20, or 30 mg / m² of body surface area. 2 It is administered in the following dose. In some embodiments, prinabulin is approximately 20 mg / m² of body surface area. 2 It is administered in the following dosage.

[0018] In some embodiments, the dose of prinabulin is approximately 5 mg to 100 mg, or approximately 10 mg to 80 mg. In some embodiments, the dose of prinabulin is approximately 15 mg to 100 mg, or approximately 20 mg to 80 mg. In some embodiments, prinabulin is administered in doses ranging from approximately 15 mg to 60 mg. In some embodiments, the dose of prinabulin is approximately 0.5 mg to 3 mg, 0.5 mg to 2 mg, 0.75 mg to 2 mg, 1 mg to 10 mg, 1.5 mg to 10 mg, 2 mg to 10 mg, 3 mg to 10 mg The dosages are 4mg-10mg, 1mg-8mg, 1.5mg-8mg, 2mg-8mg, 3mg-8mg, 4mg-8mg, 1mg-6mg, 1.5mg-6mg, 2mg-6mg, 3mg-6mg, or approximately 4mg-6mg. In some embodiments, prinabulin is administered at approximately 2mg-6mg or 2mg-4.5mg. In some embodiments, prenabulin is administered in doses of approximately 5mg-7.5mg, 5mg-9mg, 5mg-10mg, 5mg-12mg, 5mg-14mg, 5mg-15mg, 5mg-16mg, 5mg-18mg, 5mg-20mg, 5mg-22mg, 5mg-24mg, 5mg-26mg, 5mg-28mg, 5mg-30mg, 5mg-32mg, 5mg-34mg, 5mg-36mg, 5mg-38mg, 5mg-40mg, 5mg-42mg, 5mg-44mg, 5mg~46mg, 5mg~48mg, 5mg~50mg, 5mg~52mg, 5mg~54mg, 5mg~56mg, 5mg~58mg, 5mg~60mg, 7mg~7.7mg, 7mg~9mg, 7mg~10mg, 7mg~12m g, 7mg~14mg, 7mg~15mg, 7mg~16mg, 7mg~18mg, 7mg~20mg, 7mg~22mg, 7mg~24mg, 7mg~26mg, 7mg~28mg, 7mg~30mg, 7mg~32mg, 7mg~3 4mg, 7mg~36mg, 7mg~38mg, 7mg~40mg, 7mg~42mg, 7mg~44mg, 7mg~46mg, 7mg~48mg, 7mg~50mg, 7mg~52mg, 7mg~54mg, 7mg~56mg, 7mg ~58mg, 7mg~60mg, 9mg~10mg, 9mg~12mg, 9mg~14mg, 9mg~15mg, 9mg~16mg, 9mg~18mg, 9mg~20mg, 9mg~22mg, 9mg~24mg, 9mg~26mg, 9 mg~28mg, 9mg~30mg, 9mg~32mg, 9mg~34mg, 9mg~36mg, 9mg~38mg, 9mg~40mg, 9mg~42mg, 9mg~44mg, 9mg~46mg, 9mg~48mg, 9mg~50mg , 9mg~52mg, 9mg~54mg, 9mg~56mg, 9mg~58mg, 9mg~60mg, 10mg~12mg, 10mg~14mg, 10mg~15mg, 10mg~16mg, 10mg~18mg, 10mg~20mg,10mg~22mg、10mg~24mg、10mg~26mg、10mg~28mg、10mg~30mg、10mg~32mg、10mg~34mg、10mg~36mg、10mg~38mg、10mg~40mg、10mg~42mg、10mg~44mg、10mg~46mg、10mg~48mg、10mg~50mg、10mg~52mg、10mg~54mg、10mg~56mg、10mg~58mg、10mg~60mg、12mg~14mg、12mg~15mg、12mg~16mg、12mg~18mg、12mg~20mg、12mg~22mg、12mg~24mg、12mg~26mg、12mg~28mg、12mg~30mg、12mg~32mg、12mg~34mg、12mg~36mg、12mg~38mg、12mg~40mg、12mg~42mg、12mg~44mg、12mg~46mg、12mg~48mg、12mg~50mg、12mg~52mg、12mg~54mg、12mg~56mg、12mg~58mg、12mg~60mg、15mg~16mg、15mg~18mg、15mg~20mg、15mg~22mg、15mg~24mg、15mg~26mg、15mg~28mg、15mg~30mg、15mg~32mg、15mg~34mg、15mg~36mg、15mg~38mg、15mg~40mg、15mg~42mg、15mg~44mg、15mg~46mg、15mg~48mg、15mg~50mg、15mg~52mg、15mg~54mg、15mg~56mg、15mg~58mg、15mg~60mg、15mg~120mg、17mg~18mg、17mg~20mg、17mg~22mg、17mg~24mg、17mg~26mg、17mg~28mg、17mg~30mg、17mg~32mg、17mg~34mg、17mg~36mg、17mg~38mg、17mg~40mg、17mg~42mg、17mg~44mg、17mg~46mg、17mg~48mg、17mg~50mg、17mg~52mg、17mg~54mg、17mg~56mg、17mg~58mg、17mg~60mg、20mg~22mg、20mg~24mg、20mg~26mg、20mg~28mg、20mg~30mg、20mg~32mg、20mg~34mg、20mg~36mg、20mg~38mg、20mg、 ~40mg、20mg~42mg、20mg~44mg、20mg~46mg、20mg~48mg、20mg~50mg、20mg~52mg、20mg~54mg、20mg~56mg、20mg~58mg、20mg~60mg、22mg~24mg、22mg~26mg、22mg~28mg、22mg~30mg、22mg~32mg、22mg~34mg、22mg~36mg、22mg~38mg、22mg~40mg、22mg~42mg、22mg~44mg、22mg~46mg、22mg~48mg、22mg~50mg、22mg~52mg、22mg~54mg、22mg~56mg、22mg~58mg、22mg~60mg、25mg~26mg、25mg~28mg、25mg~30mg、25mg~32mg、25mg~34mg、25mg~36mg、25mg~38mg、25mg~40mg、25mg~42mg、25mg~44mg、25mg~46mg、25mg~48mg、25mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg、27mg~44mg、27mg~46mg、27mg~48mg、27mg~50mg、27mg~52mg、27mg~54mg、27mg~56mg、27mg~58mg、27mg~60mg、30mg~32mg、30mg~34mg、30mg~36mg、30mg~38mg、30mg~40mg、30mg~42mg、30mg~44mg、30mg~46mg、30mg~48mg、30mg~50mg、30mg~52mg、30mg~54mg、30mg~56mg、30mg~58mg、30mg~60mg、33mg~34mg、33mg~36mg、33mg~38mg、33mg~40mg、33mg~42mg、33mg~44mg、33mg~46mg、33mg~48mg、33mg~50mg、33mg~52mg、33mg~54mg、33mg~56mg、33mg~58mg、33mg~60mg、36mg~38mg、36mg~40mg、36mg~42mg、36mg~44mg、36mg~46mg、36mg~48mg、36mg~50mg, 36mg~52mg, 36mg~54mg, 36mg~56mg, 36mg~58mg, 36mg~60mg, 40mg~42mg, 40mg~44mg, 40mg~46mg, 40mg~48mg, 40mg~50mg, 40mg~52 mg, 40mg~54mg, 40mg~56mg, 40mg~58mg, 40mg~60mg, 43mg~46mg, 43mg~48mg, 43mg~50mg, 43mg~52mg, 43mg~54mg, 43mg~56mg, 43mg~58mg, 42mg It is administered in doses of ~60mg, 45mg~48mg, 45mg~50mg, 45mg~52mg, 45mg~54mg, 45mg~56mg, 45mg~58mg, 45mg~60mg, 48mg~50mg, 48mg~52mg, 48mg~54mg, 48mg~56mg, 48mg~58mg, 48mg~60mg, 50mg~52mg, 50mg~54mg, 50mg~56mg, 50mg~58mg, 50mg~60mg, 52mg~54mg, 52mg~56mg, 52mg~58mg, or 52mg~60mg. In some embodiments, the dose of prinabulin is approximately 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, approximately 10 mg, approximately 12.5 mg, approximately 13.5 mg, approximately 15 mg, approximately 17.5 mg, approximately 20 mg, approximately 22.5 mg, approximately 25 mg, approximately 27 mg, approximately 30 mg, or greater than approximately 40 mg. In some embodiments, the dose of prinabulin is approximately 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, approximately 10 mg, approximately 12.5 mg, approximately 13.5 mg, approximately 15 mg, approximately 17.5 mg, approximately 20 mg, approximately 22.5 mg, approximately 25 mg, approximately 27 mg, approximately 30 mg, approximately 40 mg, or less than approximately 50 mg.

[0019] In some embodiments, the dose of prinabulin is 40 mg.

[0020] In various embodiments, prinabulin is administered once, twice, or three times during a PARP inhibitor treatment cycle. In other embodiments, prinabulin is administered once daily, twice daily, three times daily, four times daily, every other day, once weekly, twice weekly, three times weekly, every other week, once every two weeks, and once every three weeks. PARP inhibitors

[0021] PARP inhibitors for use as described in this disclosure may include any agents that inhibit the activity of poly(ADP-ribose) polymerase, such as small molecules or biological agents. Specific PARP inhibitors that can be used as described in this disclosure include talazoparib (e.g., TALZENNA), niraparib (e.g., ZEJULA), olaparib (e.g., LYNPARZA), rucaparib (e.g., RUBRACA), veliparib (ABT-888), pamiparib (e.g., PARTRUVIX), NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397. Accordingly, some embodiments involve the combined administration of prinabulin and talazoparib. In some embodiments, the PARP inhibitor is not olaparib.

[0022] In some embodiments, the dose of the PARP inhibitor used is the dose at which the PARP inhibitor exerts a therapeutic effect as a monotherapy. In other embodiments, the dose of the PARP inhibitor used in combination therapy is lower than the dose at which it exerts a therapeutic effect as a monotherapy.

[0023] In various embodiments, the dose of PARP inhibitor administered is 0.1 mg to 4000 mg, 0.25 mg to 3500 mg, 0.25 mg to 3000 mg, 0.25 mg to 2500 mg, 0.25 mg to 2000 mg, 0.25 mg to 1500 mg, 0.25 mg to 1000 mg, 0.25 mg to 600 mg, 0.5 mg to 600 mg, 0.75 mg to 600 mg, 1 mg to 600 mg, 150 mg to 600 mg, 200 mg to 600 mg, 300 mg to 600 mg, 0 The dosages range from 0.5mg to 500mg, 0.5mg to 200mg, 0.75mg to 200mg, 1.0mg to 100mg, 1.5mg to 100mg, 2.0mg to 100mg, 3.0mg to 100mg, 4.0mg to 100mg, 1.0mg to 80mg, 1.5mg to 80mg, 2.0mg to 80mg, 3.0mg to 80mg, 4.0mg to 80mg, 1.0mg to 60mg, 1.5mg to 60mg, 2.0mg to 60mg, 3.0mg to 60mg, or approximately 4.0mg to 60mg.

[0024] In various embodiments, the PARP inhibitor is administered once daily, twice daily, three times daily, four times daily, every other day, once a week, once every two weeks, and once every three weeks.

[0025] In various embodiments, the dose of talazoparib administered is 0.1 mg to 5 mg, 0.25 mg to 5 mg, 0.2 mg to 4 mg, 0.25 mg to 3 mg, 0.5 mg to 2 mg, 0.75 mg to 1.5 mg, or about 1 mg. In some embodiments, the dose of talazoparib is 0.25 mg. In some embodiments, the dose of talazoparib is 0.5 mg. In some embodiments, the dose of talazoparib is 0.75 mg. In some embodiments, the dose of talazoparib is 1 mg. In some embodiments, talazoparib is administered once daily. In some embodiments, talazoparib is administered twice daily.

[0026] In various embodiments, the dose of niraparib administered is 50 mg to 500 mg, 100 mg to 400 mg, 150 mg to 350 mg, or 200 mg to 300 mg. In some embodiments, the dose of niraparib is 200 mg. In some embodiments, the dose of niraparib is 300 mg. In some embodiments, niraparib is administered once daily. In some embodiments, the dose of niraparib is 300 mg. In some embodiments, niraparib is administered twice daily.

[0027] In various embodiments, the dose of olaparib administered is 50 mg to 500 mg, 75 mg to 400 mg, 100 mg to 350 mg, or 100 mg to 300 mg. In some embodiments, the dose of olaparib is 100 mg. In some embodiments, the dose of olaparib is 150 mg. In some embodiments, the dose of olaparib is 300 mg. In some embodiments, olaparib is administered once daily. In some embodiments, olaparib is administered twice daily.

[0028] In various embodiments, the dose of rucaparib administered is 50 mg to 500 mg, 100 mg to 1000 mg, 200 mg to 800 mg, or 300 mg to 600 mg. In some embodiments, the dose of rucaparib is 300 mg. In some embodiments, the dose of rucaparib is 400 mg. In some embodiments, the dose of rucaparib is 500 mg. In some embodiments, the dose of rucaparib is 600 mg. In some embodiments, rucaparib is administered once daily. In some embodiments, rucaparib is administered twice daily.

[0029] In various embodiments, the dose of pamiparib administered is 10 mg to 100 mg, 30 mg to 80 mg, 50 mg to 70 mg, or about 60 mg. In some embodiments, the dose of pamiparib is 60 mg. In some embodiments, pamiparib is administered once daily. In some embodiments, pamiparib is administered twice daily. Pharmaceutical composition

[0030] In some embodiments, prinabulin and the PARP inhibitor are administered in the same pharmaceutical composition. In other embodiments, prinabulin and the PARP inhibitor are administered in separate pharmaceutical compositions.

[0031] The pharmaceutical compositions of this disclosure may be administered by any accepted mode of administration, including but not limited to oral, sublingual, buccal, subcutaneous, intravenous, intranasal, topical, transdermal, intradermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the pharmaceutical compositions are administered orally and / or parenterally. In some embodiments, prinabulin is administered intravenously, and the PARP inhibitor is administered orally.

[0032] In various embodiments, a pharmaceutical composition comprises an active ingredient (e.g., prinabulin and / or a PARP inhibitor) and one or more pharmaceutically acceptable carriers or excipients. The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” include any solvent, dispersion medium, coating agent, antimicrobial and antifungal agent, isotonic agent and absorption retarder, etc. The use of such media and agents with pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is intended unless conventional media or agents are incompatible with the active ingredient. Furthermore, various adjuvants commonly used in the art may be included. Considerations regarding the inclusion of various components in pharmaceutical compositions are, for example, in Gilman et al. (ed.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0033] Some examples of substances that can function as pharmaceutically acceptable carriers or components thereof include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; tragacanth powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; propylene glycol, glycerin, sorbitol, mannitol, and polyethylene. These include polyols such as glycols; alginic acid; emulsifiers such as TWEENS; humectants such as sodium lauryl sulfate; colorants; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline solution; and phosphate buffer.

[0034] The compositions of this disclosure are preferably provided in unit dosage forms. As used in this disclosure, “unit dosage form” means a composition containing an amount of the compound or composition suitable for a single dose to an animal, preferably mammalian, subject, in accordance with good medical practice. However, the preparation of a single dose or unit dosage form does not mean that the dosage form is administered once a day or once during a course of treatment. Such dosage forms are intended to be administered once, twice, three or more times a day and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2 to 6 hours) or as a continuous infusion, and may be administered multiple times during a course of treatment, but single doses are not particularly excluded. Those skilled in the art will recognize that the formulation is not specifically intended to be an entire course of treatment, and that such determination is left to those skilled in the art of the treatment, not the formulation.

[0035] Depending on the desired specific route of administration, a variety of pharmaceutically acceptable carriers known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Any pharmaceutically active substance that does not substantially interfere with the inhibitory activity of the compound or composition may be included. The amount of carrier used in conjunction with the compound or composition is sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for creating useful dosage forms by the methods of this disclosure are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0036] Various oral dosage forms are available, including solid forms such as tablets, capsules (e.g., hard capsules and soft capsules), granules, and powders. In some embodiments, PARP inhibitors are provided in such oral dosage forms. Tablets contain a suitable binder, lubricant, diluent, disintegrant, colorant, flavoring agent, fluidizer, and melting agent, and may be compressed tablets, tablet triturates, enteric coated tablets, sugar-coated tablets, film-coated tablets, or multilayer tablets. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent formulations reconstituted from effervescent granules, which contain a suitable solvent, preservative, emulsifier, suspending agent, diluent, sweetener, melting agent, colorant, and flavoring agent.

[0037] Tablets typically contain conventional pharmaceutically compatible adjuvants, such as inert diluents like calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders like starch, gelatin, and sucrose; disintegrants like starch, alginic acid, and croscarmellose; and lubricants like magnesium stearate, stearic acid, and talc. Flowing agents such as silicon dioxide can be used to improve the flow properties of powder mixtures. Colorants such as FD&C dyes can be added for appearance. Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful adjuvants for chewable tablets. Capsules typically contain one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations such as taste, cost, and storage stability, but these are not critical and can be easily determined by those skilled in the art.

[0038] Oral compositions also include liquid solutions, emulsions, and suspensions. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. In the case of formulations, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate; typical humectants include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components such as sweeteners, flavoring agents, and colorants disclosed above.

[0039] Such compositions may also be coated by conventional methods, typically with a pH or time-dependent coating, thereby releasing the composition in the gastrointestinal tract near the desired application site, or at various times to extend the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hypromellose phthalate, ethylcellulose, eudragit coating, wax, and shellac.

[0040] Other compositions useful for achieving systemic delivery of the target compound include sublingual, intrabuccal, and nasal dosage forms. Such compositions typically include one or more soluble fillers such as sucrose, sorbitol, and mannitol; as well as binders such as gum arabic, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. Fluidizers, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.

[0041] Liquid compositions formulated for topical ophthalmic use are formulated for topical administration to the eye. Comfort can be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may require a level of comfort that is not optimal. If comfort cannot be maximized, the liquid may be formulated to be acceptable to the patient for topical ophthalmic use. Furthermore, ophthalmally acceptable liquids may be packaged for single use or may contain preservatives to prevent contamination over multiple uses.

[0042] For ophthalmic use, solutions or drugs are often prepared using physiological saline as the primary vehicle. Ophthalmic solutions may preferably be maintained at a comfortable pH using an appropriate buffering system. Formulations may also contain conventionally pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0043] Preservatives that may be used in the pharmaceutical compositions of this disclosure include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercury acetate, and phenylmercury nitrate. A useful surfactant is, for example, Tween 80. Similarly, a variety of useful vehicles may be used in the ophthalmic formulations of this disclosure. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0044] Isotonic agents may be added as needed or for convenience. These include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmologically acceptable isotonic agent.

[0045] Various buffers and pH adjusting agents can be used, provided that the resulting formulation is ophthalmologically acceptable. In many compositions, the pH is in the range of 4 to 9. Therefore, buffers include acetate buffer, citrate buffer, phosphate buffer, and borate buffer. Acids or bases can be used as needed to adjust the pH of these formulations.

[0046] Ophthalmologically acceptable antioxidants include sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. These are rare, but not limited to them.

[0047] Other excipients that may be included in ophthalmic preparations are chelating agents. A useful chelating agent is disodium edetate, but other chelating agents may be used in place of or in combination with it.

[0048] For topical use, creams, ointments, gels, solutions, or suspensions containing the compositions of this disclosure may be used. Topical formulations may generally consist of a pharmaceutical carrier, a co-solvent, an emulsifier, a penetration enhancer, a preservative, and a emollient.

[0049] For intravenous administration, the compositions of this disclosure may be dissolved or dispersed in a pharmaceutically acceptable diluent such as physiological saline or glucose solution. To achieve the desired pH, suitable excipients may be included, but are not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition is in the range of 2 to 8, preferably 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as glucose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated in their entirety by reference. Antimicrobial agents, including but not limited to phenylmercury nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol, may also be included to achieve bacteriostatic or fungiostatic solutions.

[0050] The composition for intravenous administration may be provided to the caregiver in the form of one or more solids that are reconstituted immediately before administration with a suitable diluent such as sterile water, physiological saline, or glucose aqueous solution. In another embodiment, the composition is provided in the form of a parenterally administered solution. In yet another embodiment, the composition is provided in the form of a solution that is further diluted before administration.

[0051] In some embodiments, prinabulin for intravenous administration is provided as a pharmaceutical composition comprising one or more pharmaceutically acceptable diluents. In some embodiments, the pharmaceutically acceptable diluent may comprise Kolliphor® (polyethylene glycol (15)-hydroxystearate). In some embodiments, the pharmaceutically acceptable diluent may comprise propylene glycol. In some embodiments, the pharmaceutically acceptable diluent may comprise Kolliphor (Kolliphor HS 15) and propylene glycol. In some embodiments, the pharmaceutically acceptable diluent comprises Kolliphor and propylene glycol, where Kolliphor is present in about 40% by weight of the total weight of the diluent and propylene glycol in about 60% by weight. In some embodiments, the composition may further comprise one or more other pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition may be diluted before administration, for example, with water, saline, or D5W (5% glucose solution). Treatment method

[0052] In some embodiments, prinabulin and PARP inhibitors are administered in combination to treat cancer. In various embodiments, the cancer includes homologous recombination repair deficiency tumors. In some embodiments, the cancer includes mutations in homologous recombination repair genes. In some embodiments, the cancer includes BRCA1 and / or BRCA2 mutations. In various embodiments, The cancers included ovarian cancer, breast cancer, lung cancer, pancreatic cancer, fallopian tube cancer, primary peritoneal cancer, and prostate cancer.

[0053] In some embodiments, prinabulin is administered after the administration of a PARP inhibitor. In other embodiments, prinabulin is administered before or concurrently with the administration of a PARP inhibitor. In some embodiments, prinabulin is administered 1 minute to 5 hours, 5 minutes to 4 hours, 10 minutes to 3.5 hours, 30 minutes to 3 hours, 30 minutes to 2 hours, 30 minutes to 1.5 hours, 1 hour to 2.5 hours, about 1 hour, or about 2 hours after the administration of a PARP inhibitor. In some embodiments, prinabulin is administered 1 minute to 5 hours, 5 minutes to 4 hours, 10 minutes to 3.5 hours, 30 minutes to 3 hours, 30 minutes to 2 hours, 30 minutes to 1.5 hours, 1 hour to 2.5 hours, about 1 hour, or about 2 hours before the administration of a PARP inhibitor.

[0054] In some embodiments, prinabulin is administered on the same day that PARP inhibitor therapy is initiated. In other embodiments, prinabulin is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, and / or 10 days after the initiation of PARP inhibitor therapy.

[0055] In some embodiments of the treatment method, farnesyl pyrophosphate synthase (FPPS) inhibitors are not administered concomitantly with prinabulin and PARP inhibitors. In some embodiments of the treatment method, immune checkpoint inhibitors (e.g., pembrolizumab) are not administered concomitantly with prinabulin and PARP inhibitors. In some embodiments, subjects receiving concomitant administration of prinabulin and PARP inhibitors have not received prior treatment with immune checkpoint inhibitors. In some embodiments of the treatment method, compounds having the structure of formula (I) are not administered concomitantly with prinabulin and PARP inhibitors: [ka] During the ceremony: R 1 -COOH, -COOR 1a ,-COO(CH2) m C(O)NR 1a R 2a -CONHR 1b , -COR 4 , or -CONH(CH2) m COOR 2b and; R 2 -CH(O) or -CH(=NOR 1a ) and; R 3 H, -C(O)R 1a , even if it is substituted -C 1-10 Alkyl alkyl groups, or substituted C 2-10 Alkenyl group, may be substituted C 2-10 Alkynyl group, may be substituted C 3-7 Cycloalkyl groups, optionally substituted 3-8 membered heterocyclyl groups, optionally substituted 5-6 membered monosaccharide rings, optionally substituted C 6-10 An aryl group, or a substituted 5-10 membered heteroaryl group; R 4 This is an amino acid residue linked via the N-terminal amine; R 1a , R 2a , R 1b and R 2bThese are, independently, -H, halogen, -OH, -COOH, and -COO(C) 1-4 C (alkyl group), may be substituted. 1-10 Alkyl alkyl groups, or substituted C 2-10 Alkenyl group, may be substituted C 2-10 Alkynyl group, may be substituted C 3-7 Cycloalkyl groups, optionally substituted 3-8 membered heterocyclyl groups, optionally substituted 5-6 membered monosaccharide rings, optionally substituted C 6-10 Selected from an aryl group or a substituted 5-10 membered heteroaryl group; and m is an integer between 0 and 3.

[0056] In some embodiments of the treatment method, compounds having the structure of formula (II) are not administered in combination with prinabulin and PARP inhibitors: [ka] During the ceremony: Y 1 C is a hydroxyl group. 1-4 Alkylamino group, and its C 1-4 Selected from acylamino groups having an alkyl moiety; Y 2 , Y 3 and Y 4 These are independently hydrogen, halogen, and C 1-4 Alkyl alkyl group, C 1-4 Selected from alkoxy groups, trifluoromethyl groups, hydroxyl groups, and benzyloxy groups; and Q 1 teeth, [ka] It is one of the following, and here, Q 2 and Q 3 Hydrogen and C are independent of each other. 1-4 Selected from alkyl groups; X is a cyano group, a carboxyl group or its derivative, a 5-tetrazolyl group, and its C 1-6Selected from alkylsulfonylcarbamyl groups having an alkyl moiety; and n is an integer selected from 0 or 1, 2, 3, 4, 5, or 6.

[0057] To further illustrate the present invention, the following embodiments are included. Of course, these embodiments should not be construed as specifically limiting the invention. Variations of these embodiments within the scope of the claims are within the authority of those skilled in the art and are deemed to be described in this disclosure and included within the scope of the claimed invention. Readers will recognize that those skilled in the art, with the skills of this disclosure and the art, can prepare and use the present invention without exhaustive embodiments. [Examples]

[0058] The antitumor activity of prinabulin monotherapy was evaluated in a xenograft model of MDA-MB-231 human breast cancer in athymic nude mice, compared to its combination therapy with talazoparib.

[0059] Prinabulin was provided as a 4 mg / mL solution in 40% Solutol and 60% propylene glycol. Before use, this solution was diluted with D5W and gently mixed to obtain a clear solution with a concentration of 0.75 mg / mL, and a dose of 7.5 mg / kg was administered at a dosing volume of 10 mL / kg.

[0060] Talazoparib was provided as a crystalline solid. Before administration, an appropriate amount of talazoparib solid was weighed and dissolved in DMA. Then, Kolliphor(Solutol)HS15 and PBS were added sequentially to obtain a solution with a final ratio of 10% DMA, 5% Kolliphor(Solutol)HS, and 85% PBS at a concentration of 0.0165 mg / mL. Talazoparib was administered as a clear solution at a concentration of 0.0165 mg / mL at a dosing volume of 10 mL / kg, at a dose of 0.165 mg / kg.

[0061] The vehicle controls were 8% Kolliphor (Solutol) HS15, 12% propylene glycol, and 80% D5W, each freshly prepared before administration. The vehicle controls were administered intraperitoneally at a dose volume of 10 mL / kg.

[0062] The MDA-MB-231 human breast cancer tumor cell line was maintained in RPMI-1640 containing 5% FBS and 1% penicillin / streptomycin. Cells were cultured under a 5% CO2 atmosphere. The cultures were grown in tissue culture flasks at a 1:5 split ratio until a sufficient number of cells were harvested. Cells were harvested using a 0.25% trypsin / EDTA mixture.

[0063] Female athymic nude mice (Crl:NU(NCr)-Foxn1nu) were accepted at 5 weeks of age. All mice were acclimatized for at least 5-7 days before the start of the study. Mice were housed in micro-isolater cages and maintained under specific pathogen-free conditions. Mice were fed Teklad Global Diet 2920x irradiated animal feed, and autoclaved water was freely available. DietGel 76A was provided as a nutritional supplement as needed.

[0064] Female mice were anesthetized with isoflurane and had 1 × 10⁶ pieces placed in the right inguinal mammary fat pad. 7 Mice were inoculated with 0.1 mL of a 50% RPMI-1640 / 50% Matrigel mixture containing a suspension of live MDA-MB-231 tumor cells (1 / mice). At the time of inoculation, the mice were 6 weeks old.

[0065] Tumor-carrying animals were monitored, and tumors were measured regularly until they reached a specified starting size. At 28 days post-inoculation, tumor sizes ranged from 76 to 128 mm. 3 The 40 mice each measured an average of 96 mm. 3The mice were randomly assigned to four groups of 10 each. Tumor volume and body weight were recorded when the mice were randomized and then measured twice a week thereafter. Clinical observations were performed daily. Administration was via intraperitoneal injection for the vehicle control and prinabulin, and orally and intragastricly for talazoparib as described in Table 1 below. Talazoparib was administered twice daily (BID) at 8-hour intervals. Prinabulin was administered one hour after the morning dose of talazoparib on days of concomitant administration. [Table 1]

[0066] In mice, the individual tumor volume is 1,500 mm³. 3 The mice were euthanized once they reached the above threshold. The experiment ended on day 60, and all remaining mice that did not reach the tumor volume endpoint were euthanized as long-term survivors (LTS).

[0067] At the endpoint or end of the study (day 60), the mice were euthanized and the tumors were removed. The wet weight of the tumors was recorded, and the tissue was subsequently discarded.

[0068] The average TGI (tumor growth inhibition rate) was calculated using the following formula on day 33, the final day of the study in which all mice participated. All mice were included in the TGI calculation.

number

[0069] All statistical analyses in the xenotransplantation trials were performed using GraphPad Prism software. A p ≤ 0.05 value was considered statistically significant.

[0070] Differences in tumor volume and percentage change in body weight on days 33, 43, and 51 were confirmed by one-way analysis of variance (ANOVA) (unpaired, parametric) with Tukey's multiple comparison test. Two-sided Student's t-tests with Welch's correction were also used to examine differences between each group and the vehicle control group, as well as between the monotherapy groups and their respective combination therapy groups.

[0071] Increased survival rates were confirmed by log-rank tests comparing each treatment group with the vehicle control group. All animals that reached individual tumor volume endpoints or were euthanized as LTS were included in the statistical analysis. Using these data, the mean and median survival times for each group were calculated, and log-rank comparisons were performed. For the purpose of statistical analysis, animals euthanized as LTS were included. The date of death for Su was set as the 60th day.

[0072] The vehicle control group [Group 1] had a mean tumor volume of 1004.7 mm on day 33. 3 The median survival time for this group was 42 days (minimum: 33, maximum: 60). Nine out of ten mice were euthanized when they reached their individual tumor volume endpoint. The remaining mouse was euthanized on day 60 and recorded as a long-term survivor. At necropsy, the mean wet tumor weight in this group was 1,136.5 mg (n=10), with a minimum individual tumor weight of 652 mg and a maximum individual tumor weight of 1,838 mg.

[0073] Treatment with talazoparib 0.165 mg / kg [Group 2] resulted in a mean tumor volume of 405.7 mm² at day 33. 3This group showed a 65.9% TGI (transient growth index) compared to the vehicle control group on day 33 (n=10). A statistically significant reduction in mean tumor volume was observed compared to the vehicle control group on days 33 and 43 (ANOVA and Student's t-test; p<0.05). The median survival time for this group was 60 days (minimum: 51, maximum: 60). A statistically significant extension of survival time was observed compared to the vehicle control group. Four out of ten mice were euthanized when they reached their individual tumor volume endpoints. The remaining six mice were euthanized on day 60 and recorded as long-term survivors. At necropsy, the mean wet tumor weight of this group was 1,040.4 mg (n=10), with a minimum individual tumor weight of 591 mg and a maximum individual tumor weight of 1,703 mg.

[0074] Treatment with prinabulin 7.5 mg / kg [Group 3] resulted in a mean tumor volume of 385.2 mm² at day 33. 3 This group showed a 68.2% TGI (tissue growth index) compared to the vehicle control group on day 33 (n=10). A statistically significant reduction in mean tumor volume was observed compared to the vehicle control group on days 33 and 43 (ANOVA and Student's t-test; p<0.05). No significant difference in mean tumor volume was observed on days 33, 43, and 51 compared to the talazoparib monotherapy group (group 2). The median survival time for this group was 60 days (minimum: 51, maximum: 60). Two out of 10 mice were euthanized when they reached their individual tumor volume endpoints. Mouse 3 was euthanized on day 46 due to severe abdominal distension. The remaining seven mice were euthanized on day 60 and recorded as long-term survivors. At autopsy, the average wet tumor weight in this group was 721.9 mg (n=10), with a minimum individual tumor weight of 371 mg and a maximum individual tumor weight of 1,250 mg.

[0075] Treatment with talazoparib 0.165 mg / kg + prinabulin 7.5 mg / kg [Group 4] resulted in a mean tumor volume of 363.5 mm² at day 33. 3This group showed a 70.6% TGI (tissue growth index) compared to the vehicle control group on day 33 (n=10). A statistically significant reduction in mean tumor volume was observed compared to the vehicle control group on days 33, 43, 51, and 60 (ANOVA and Student's t-test; p<0.05). Furthermore, a statistically significant reduction in mean tumor volume was observed on days 43 and 60 compared to the talazoparib monotherapy group (group 2) (Student's t-test; p<0.05). However, no significant difference in mean tumor volume was observed on days 33 and 51 compared to the talazoparib monotherapy group (group 2). In addition, no significant difference in mean tumor volume was observed on days 33, 43, 51, and 60 compared to the prinabulin monotherapy group (group 3). The median survival time for this group was 60 days (minimum: 60, maximum: 60).

[0076] Figure 1 shows the effect of various treatments on the mean tumor volume (carryover of the final tumor volume). Figure 2 shows the mean wet tumor weight obtained in vitro at the end of the study. Notably, combination therapy (group 4) showed the greatest effect, with a 71% TGI on day 33. Talazoparib monotherapy (group 2) and prinabulin monotherapy (group 3) showed TGIs of 66% and 68%, respectively, on day 33.

[0077] Efficacy was also evaluated by tumor growth delay (survival time) compared to the vehicle control group. Figure 3 shows the impact of treatment on survival, including tumor-related deaths only. Treatment with talazoparib (group 2), prinabulin (group 3), and talazoparib + prinabulin (group 4) all resulted in a median survival of 60 days, an extension of 18 days compared to the vehicle control group. Talazoparib + prinabulin (group 4) showed a tumor volume endpoint (≥1,500 mm) by day 60. 3 It was remarkable that not a single mouse reached the 50% level.

[0078] These results demonstrate improved efficacy with the combination of talazoparib and prinabulin. While not bound by a single theory of action, combinations of these types of drugs enable complementary mechanisms of action, leading to more effective suppression of tumor growth than either drug alone. In some embodiments, the combinations according to this disclosure may achieve synergistic anticancer effects by leveraging the different mechanisms of action of the disclosed drugs. For example, prinabulin's interference with microtubule dynamics may enhance the accumulation of DNA damage by simultaneously interfering with cell division, while a PARP inhibitor may exacerbate the cellular impairment of this damage. In some embodiments, this combination may result in increased DNA damage and lead to enhanced apoptosis (programmed cell death) in cancer cells. Furthermore, combinations of prinabulin, a PARP inhibitor, and optionally one or more anticancer compounds may help overcome resistance to monotherapy or dual therapy. These therapeutic combinations may also extend the therapeutic effects of one or more of the compounds according to this disclosure to a wider range of cancers.

[0079] Figure 4 shows the effect of different treatments on weight change over time and can be used as a surrogate indicator for evaluating drug toxicity in animal studies. Group 1 was the vehicle control and showed healthy weight gain, suggesting no drug-induced toxicity. Group 2, treated with talazoparib, and Group 3, treated with prinabulin, also showed some weight gain compared to Group 1. Group 4, which received talazoparib and prinabulin in combination, also showed weight gain. Despite the possibility that administration of the two drugs could cause greater weight change due to additive toxic effects, the profile of this group was similar to that of the control group, indicating that this combination did not exacerbate toxicity compared to the use of either drug alone. This result may be counterintuitive, as it might be expected that combining the two drugs would increase overall toxicity.

[0080] Therefore, in some embodiments, the combination of talazoparib and prinabulin may mitigate the side effects commonly associated with PARP inhibitors such as talazoparib. Furthermore, in some embodiments, the combination of talazoparib and prinabulin may mitigate neutropenia, a common side effect of cancer treatment with PARP inhibitors that results in a decrease in white blood cell count.

[0081] Figure 4 also suggests that a higher total drug dose can be administered without increased side effects, as the combination therapy group maintained a similar body weight to the control group. Therefore, in some embodiments, this disclosure provides more flexible dosing regimens that achieve therapeutic effects without the increased toxicity typically associated with higher total drug doses.

Claims

1. A method for treating cancer, comprising administering prinabulin and a PARP inhibitor in combination to a subject.

2. The method according to claim 1, wherein prinabulin is administered intravenously.

3. The method according to claim 1 or 2, wherein the PARP inhibitor is administered orally.

4. The method according to any one of claims 1 to 3, wherein the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, olaparib, lucaparib, veliparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397.

5. The method according to any one of claims 1 to 3, wherein the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, lucaparib, veliparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397.

6. The method according to any one of claims 1 to 3, wherein the PARP inhibitor is talazoparib.

7. The method according to claim 6, wherein talazoparib is administered in a dose of 0.25 mg to 5 mg.

8. The method according to claim 6 or 7, wherein talazoparib is administered once daily.

9. The method according to claim 6 or 7, wherein talazoparib is administered twice daily.

10. The dose of prinabulin administered is 10 mg / m². ２ ~40 mg / m² ２ The method according to any one of claims 1 to 9.

11. The method according to any one of claims 1 to 9, wherein the dose of prinabulin administered is 15 mg to 120 mg.

12. The method according to claim 11, wherein the dose of prinabulin administered is approximately 40 mg.

13. The method according to any one of claims 1 to 12, wherein prinabulin is administered once a week.

14. The method according to any one of claims 1 to 12, wherein prinabulin is administered twice a week.

15. The method according to any one of claims 1 to 12, wherein prinabulin is administered once every three weeks.

16. A pharmaceutical composition comprising prinabulin or a pharmaceutically acceptable salt thereof, and a PARP inhibitor or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition according to claim 16, wherein the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, olaparib, lucaparib, veliparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397.

18. The pharmaceutical composition according to claim 16, wherein the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, lucaparib, veliparib, pamiparib, NMS-293, E7449, CEP-9722, RP12146, IDX-1197, IMP4297, and RBN-2397.

19. The pharmaceutical composition according to claim 16, wherein the PARP inhibitor is talazoparib.

20. It's a kit, A first pharmaceutical composition comprising prinabulin or a pharmaceutically acceptable salt thereof, A second pharmaceutical composition containing a PARP inhibitor, A kit that includes this.

21. The kit according to claim 20, wherein the first pharmaceutical composition is an intravenous formulation and the second pharmaceutical composition is an oral formulation.

Images