Oncology combination therapy and methods of use

Abstract

Disclosed herein is the treatment of cancer by co-administering plinabulin and a PARP inhibitor, such as talazoparib. Some embodiments disclosed herein relate to compositions comprising plinabulin and a PARP inhibitor, such as talazoparib. Some embodiments relate to methods of treating cancer by co-administering plinabulin and one or more PARP inhibitor.

Description

ONCOLOGY COMBINATION THERAPY AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 451517, filed March 10, 2023, the content of which is incorporated by reference in its entirety.Field

[0002] The present disclosure relates to the field of chemistry and medicine. More specifically, it relates to combination therapy for the treatment of cancer.BACKGROUND

[0003] The Poly (ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including the regulation of transcription, apoptosis and the DNA damage response. Rose et al., Front. Cell Dev. Biol., 8 (2020) (https: / / doi.org / 10.3389 / fcell.2020.564601). PARP1 possesses Poly (ADP-ribose) activity and when activated by DNA damage, adds branched PAR chains to facilitate the recruitment of other repair proteins to promote the repair of DNA single-strand breaks. PARP inhibitors were the first approved cancer drugs that specifically targeted the DNA damage response in BRCA1 / 2 mutated breast and ovarian cancers. There are several approvals or trials of PARP inhibitors for use as anti-cancer therapy for ovarian, breast, lung, pancreatic, fallopian, primary peritoneal, and prostate cancers.

[0004] Despite the success of PARP inhibitor therapies, resistance to therapy is ubiquitous in the clinic. More than 40% of BRCAl / 2-deficient patients fail to respond to PARP inhibitor therapy. Li et al., Molecular Cancer, 19(107) (2020) (https: / / doi.org / 10.1186 / sl2943-020-01227-0). Thus, there exists a need for improved anticancer therapies utilizing this treatment modality.SUMMARY OF THE INVENTION

[0005] Some embodiments described herein include a method of treating cancer, comprising co-administering to a subject in need thereof plinabulin and a PARP inhibitor. In some embodiments, plinabulin 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 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. In some embodiments, talazoparib is administered at a dose of 0.25 mg to 5 mg. In some embodiments, alazoparib is administered once per day. In some embodiments, talazoparib is administered twice per day. In some embodiments, the dose of plinabulin administered is from 10 mg / m2to 40 mg / m2. In some embodiments, the dose of plinabulin administered is from 15 mg to 120 mg. In some embodiments, the dose of plinabulin administered is about 40 mg. In some embodiments, plinabulin is administered once per week. In some embodiments, plinabulin is administered twice per week. In some embodiments, plinabulin is administered once every three weeks.

[0006] Some embodiments described herein include a pharmaceutical composition, comprising plinabulin or a pharmaceutically acceptable salt thereof and a PARP inhibitor or a pharmaceutically acceptable salt thereof. 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 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 described herein include a kit, comprising: a first pharmaceutical composition comprising plinabulin 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 formulation and the second pharmaceutical composition is an oral formulation.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 is a graph showing the mean tumor volume in a MDA-MB-231 human breast cancer xenograft model upon administration of vehicle control, talazoparib alone, plinabulin alone, and the combination of plinabulin and talazoparib.

[0010] Figure 2 is a bar graph showing the combined tumor wet weight at death in a MDA-MB-231 human breast cancer xenograft model upon administration of vehicle control, talazoparib alone, plinabulin alone, and the combination of plinabulin and talazoparib.

[0011] Figure 3 is a graph showing animal survival in a MDA-MB-231 human breast cancer xenograft model upon administration of vehicle control, talazoparib alone, plinabulin alone, and the combination of plinabulin and talazoparib.

[0012] Fig. 4 is a graph showing the effect of different treatments on body weight change over time.DETAILED DESCRIPTION

[0013] Disclosed herein are methods for treating cancer. In some embodiments, the methods include co-administration of plinabulin and a poly (ADP-ribose) polymerase (PARP) inhibitor. Administration of plinabulin herein includes administering a pharmaceutically acceptable salt or solvate (including hydrate) of plinabulin. In some embodiments, plinabulin is provided as a monohydrate. Administration of the PARP inhibitor herein includes administering a pharmaceutically acceptable salt of the PARP inhibitor.

[0014] The terms “pharmaceutically acceptable salts” and “a pharmaceutically acceptable salt thereof’ as used herein are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refer without limitation to salts prepared from pharmaceutically acceptable, non-toxic acids or bases. Suitable pharmaceutically acceptable salts include metallic salts, e. ., salts of aluminum, zinc, alkali metal salts such as lithium, sodium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts;organic salts, e. ., 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., sulfate, hydrochloride, and hydrobromide; and other salts which are currently in widespread pharmaceutical use and are listed in sources well known to those of skill in the art, such as, for example, The Merck Index. Any suitable constituent can be selected to make a salt of the therapeutic agents discussed herein, provided that it is non-toxic and does not substantially interfere with the desired activity.

[0015] As used herein, the terms “co-administer,” “co-administering,” or “coadministration,” refers to two or more agents or therapies that have a biological effect on a subject at the same time, regardless of when or how they are actually administered. In one embodiment, the agents or therapies are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents or therapies are administered sequentially. In some embodiments, the administration may be separated by a period of time, for example, 30 minutes, 1 hour, 2 hours, 1 day, 2 days, 3 days, or 1 week. In one embodiment the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one being administered orally and another being administered i.v.Plinabulin

[0016] Plinabulin, (3Z,6Z)-3-benzylidene-6-{[5-(2-methyl-2-propanyl)-lH- imidazol-4-yl]methylene}-2,5-piperazinedione, is a synthetic analog of the natural compound phenylahistin. Plinabulin can be readily prepared according to methods and procedures detailed in U.S. Pat. Nos. 7,064,201 and 7,919,497, which are incorporated herein by reference in their entireties.

[0017] In some embodiments, plinabulin is administered at a dose in the range of about 1-50 mg / m2of the body surface area. In some embodiments, plinabulin is administered at a dose in the range of about 5 to about 50 mg / m2of the body surface area. In some embodiments, plinabulin is administered at a dose in the range of about 20 to about 40 mg / m2of the body surface area. In some embodiments, plinabulin is administered at a dose in the range of about 15 to about 30 mg / m2of the body surface area. In some embodiments,plinabulin is administered at a dose in the range of about 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 0.5-11, 0.5-12, 0.5-13, 0.5-13.75, 0.5-14, 0.5-15, 0.5-16, 0.5-17, 0.5-18, 0.5-19, 0.5-20, 0.5-22.5, 0.5-25, 0.5-27.5, 0.5-30, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 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, 1.5-27.5, 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, of the body surface area. In some embodiments, plinabulin is administered at a dose of 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 mg / m2of the body surface area. In some embodiments, plinabulin is administered at a dose less than 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 40 mg / m2of the body surface area. In some embodiments, plinabulin is administered at a dose greater than 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 50 mg / m2of the body surface area. In some embodiments, plinabulin is administered at a dose of about10, 13.5, 20, or 30 mg / m2of the body surface area. In some embodiments, plinabulin is administered at a dose of about 20 mg / m2of the body surface area.

[0018] In some embodiments, the plinabulin dose is about 5 mg - 100 mg, or about 10 mg - 80 mg. In some embodiments, the plinabulin dose is about 15 mg - 100 mg, or about 20 mg - 80 mg. In some embodiments, plinabulin is administered at a dose in the range of about 15 mg - 60 mg. In some embodiments, the plinabulin dose is about 0.5 mg - 3 mg, 0.5 mg -2 mg, 0.75 mg - 2 mg, 1 mg - 10 mg, 1.5 mg - 10 mg, 2 mg - 10 mg, 3 mg - 10 mg, 4 mg - 10 mg, 1 mg - 8 mg, 1.5 mg - 8 mg, 2 mg - 8 mg, 3 mg - 8 mg, 4 mg - 8 mg, 1 mg - 6 mg, 1.5 mg - 6 mg, 2 mg - 6 mg, 3 mg - 6 mg, or about 4 mg - 6 mg. In some embodiments, plinabulin is administered at about 2 mg - 6 mg or 2 mg - 4.5 mg. In some embodiments, plinabulin is administered at about 5 mg-7.5 mg, 5 mg-9 mg, 5 mg-10 mg, 5 mg-12mg, 5mg- 14mg, 5mg-15 mg, 5 mg- 16 mg, 5 mg- 18 mg, 5 mg-20 mg, 5 mg-22 mg, 5 mg-24 mg, 5 mg- 26 mg, 5 mg-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, 7 mg-7.7 mg, 7 mg-9 mg, 7 mg-10 mg, 7 mg-12mg, 7mg- 14mg, 7mg-15 mg, 7 mg- 16 mg, 7 mg- 18 mg, 7 mg-20 mg, 7 mg-22 mg, 7 mg-24 mg, 7 mg- 26 mg, 7 mg-28mg, 7mg-30mg, 7mg-32mg, 7mg-34mg, 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, 9 mg-10 mg, 9 mg-12mg, 9mg-14mg, 9mg-15 mg, 9 mg-16 mg, 9 mg- 18 mg, 9 mg-20 mg, 9 mg-22 mg, 9 mg-24 mg, 9 mg-26 mg, 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, 10 mg-12mg, 10mg-14mg, 10mg-15 mg, 10 mg-16 mg, 10 mg- 18 mg, 10 mg-20 mg, 10 mg-22 mg, 10 mg-24 mg, 10 mg-26 mg, 10 mg-28mg, 10mg-30mg, 10mg-32mg, lOmg- 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-15 mg, 12 mg-16 mg, 12 mg- 18 mg, 12 mg-20 mg, 12 mg-22 mg, 12 mg-24 mg, 12 mg-26 mg, 12 mg-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, 15 mg- 16 mg, 15 mg- 18 mg, 15 mg-20 mg, 15 mg-22 mg, 15 mg-24 mg, 15 mg-26 mg, 15 mg-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, 17 mg- 18 mg, 17 mg-20 mg, 17 mg-22 mg, 17 mg-24 mg, 17 mg-26 mg, 17 mg-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, 20 mg-22 mg, 20 mg-24 mg, 20 mg-26 mg, 20 mg-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, 22 mg-24 mg, 22 mg-26 mg, 22 mg- 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, 25 mg-26 mg, 25 mg-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, 27 mg-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-52mg, 40mg-54mg, 40mg-56mg, 40mg-58mg, 40mg-60mg, 43mg-46mg, 43mg-48mg, 43mg-50mg, 43mg-52mg, 43mg-54mg, 43mg-56mg, 43mg-58mg, 42mg-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, plinabulin dose is greater than about 0.5mg, Img, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, or about 40 mg. In some embodiments, the plinabulin dose is about less than about Img, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, or about 50 mg.

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

[0020] In various embodiments, plinabulin is administered once in a PARP inhibitor treatment cycle, twice in a PARP inhibitor treatment cycle, or three times in a PARP inhibitor treatment cycle. In other embodiments plinabulin is administered once a day, twice a day, three times a day, four times a day, every other day, once a week, twice a week, three times a week, once every other week, once every two weeks, and once every three weeks.PARP Inhibitors

[0021] The PARP inhibitors for use as described herein can include any agent, including a small molecule or biological agent, that inhibits the activity of poly (ADP-ribose) polymerase. Specific PARP inhibitors that can be used as described herein 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 include co-administration of plinabulin 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 for which the PARP inhibitor is therapeutically effective as a single agent. In other embodiments, the dose of the PARP inhibitor used in the co-administration is lower than the therapeutically effective dose as a single agent.

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

[0024] In various embodiments, the PARP inhibitor is administered once a day, twice a day, three times a day, four times a day, 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 from 0.1 mg to 5 mg, from 0.25 mg to 5 mg, from 0.2 mg to 4 mg, from 0.25 mg to 3 mg, from 0.5 mg to 2 mg, from 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 from 50 mg to 500 mg, from 100 mg to 400 mg, from 150 mg to 350 mg, or from 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 from 50 mg to 500 mg, from 75 mg to 400 mg, from 100 mg to 350 mg, or from 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 from 50 mg to 500 mg, from 100 mg to 1000 mg, from 200 mg to 800 mg, or from 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 someembodiments, 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 from 10 mg to 100 mg, from 30 mg to 80 mg, from 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 Compositions

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

[0031] Administration of the pharmaceutical compositions described herein can be via any of the accepted modes of administration including, but not limited to, orally, sublingually, buccally, subcutaneously, intravenously, intranasally, topically, transdermally, intradermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. In some embodiments, the pharmaceutical compositions are administered orally and / or parenterally. In some embodiments, plinabulin is administered intravenously and the PARP inhibitor is administered orally.

[0032] In various embodiments, pharmaceutical compositions include the active agent (e.g., plinabulin and / or the PARP inhibitor) and one or more pharmaceutically acceptable carrier or excipient. The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (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, which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; 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 oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0034] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound or composition that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, although a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.

[0035] Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically- acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound or composition. The amount of carrier employed in conjunction with the compound or composition is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the followingreferences, all incorporated by reference herein: Modem 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 can be used, including such solid forms as tablets, capsules (e.g. solid gel capsules and liquid gel capsules), granules and bulk powders. In some embodiments, the PARP inhibitor is provided in such an oral dosage form. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple- compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0037] Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the 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 comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.

[0038] Oral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for 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. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodiumalginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben 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 pH or time-dependent coatings, such that the subject composition is released in the gastrointestinal tract in the vicinity of the desired application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

[0040] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0041] A liquid composition, which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye. The comfort may be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid may be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid may either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.

[0042] For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions may preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0043] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate. A usefulsurfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

[0044] Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.

[0045] Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

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

[0047] Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.

[0048] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the composition disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0049] For intravenous administration, the compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 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 phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, 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 herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0050] The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration.

[0051] In some embodiments, the plinabulin for intravenous administration is provided in a pharmaceutical composition including one or more pharmaceutically acceptable diluents. In some embodiments, the pharmaceutically acceptable diluent can include Kolliphor® (Polyethylene glycol (15)-hydroxystearate). In some embodiments, the pharmaceutically acceptable diluent can include propylene glycol. In some embodiments, the pharmaceutically acceptable diluents can include kolliphor (Kolliphor HS 15) and propylene glycol. In some embodiments, the pharmaceutically acceptable diluents can include kolliphor and propylene glycol, wherein the kolliphor is about 40% by weight and propylene glycol is about 60% by weight based on the total weight of the diluents. In some embodiments, the composition can further include one or more other pharmaceutically acceptable excipients. In some embodiments, a pharmaceutical composition can be diluted prior to administration, such as dilution with water, saline, or D5W (5% dextrose solution).Methods of Treatment

[0052] In some embodiments, plinabulin and a PARP inhibitor are coadministered to treat cancer. In various embodiments, the cancer comprises a homologous recombination repair deficient tumor. In some embodiments, the cancer comprises a mutation in a homologous recombination repair gene. In some embodiments, the cancercomprises a BRCA1 and / or BRCA2 mutation. In various embodiments, the cancer is an ovarian, breast, lung, pancreatic, fallopian, primary peritoneal, and prostate cancer.

[0053] In some embodiments, plinabulin is administered after administration of a PARP inhibitor. In other embodiments, plinabulin is administered before or simultaneously with a PARP inhibitor. In some embodiments, plinabulin is administered from 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 a PARP inhibitor. In some embodiments, plinabulin is administered from 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 a PARP inhibitor.

[0054] In some embodiments, plinabulin is administered on the same day that PARP inhibitor therapy is started. In other embodiments, plinbulin is administered on the day after, two days after, three days after, four days after, five days after, six days after, seven days after, eight days after, nine days after, and / or ten days after the start of PARP inhibitor therapy.

[0055] In some embodiments of the method of treatment, a farnesyl pyrophosphate synthase (FPPS) inhibitor is not co-administered with the plinabulin and PARP inhibitor. In some embodiments of the method of treatment, an immune checkpoint inhibitor (e g., pembrolizumab) is not co-administered with the plinabulin and PARP inhibitor. In some embodiments, the subjects being co-administered the plinabulin and PARP inhibitor did not have prior treatment with an immune checkpoint inhibitor. In some embodiments of the method of treatment, a compound having the structure of formula (I) is not co-administered with the plinabulin and PARP inhibitor:wherein:R1is COOH, COORla, COO(CH2)mC(O)NRlaR2a, CONHRlb, COR4, or -CONH(CH2)mCOOR2b;R2is -CH(O) or -CH(=NORla);R3is H, -C(O)Rla, optionally substituted -Ci-io alkyl, optionally substituted C2-ioalkenyl, optionally substituted C2-10 alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 5-6 membered monosaccharide ring, optionally substituted Ce-io aryl, or optionally substituted 5-10 membered heteroaryl;R4is an amino acid residue attached through an N-terminal amine; each Rla, R2a, Rlband R2bare independently selected from -H, halogen -OH, -COOH, -COO(Ci-4alkyl), optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 5-6 membered monosaccharide ring, optionally substituted Ce-io aryl, or optionally substituted 5-10 membered heteroaryl; and m is an integer between 0 to 3.

[0056] In some embodiments of the method of treatment, a compound having the structure of formula (II) is not co-administered with the plinabulin and PARP inhibitor:wherein:Y1is selected from hydroxyl, C1.4 alkylamino and acylamino having a C1-4 alkyl moiety thereof;Y2, Y3and Y4are independently selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, hydroxyl and benzyloxy; andQ1is either where Q2and Q3are independently selected from hydrogen and C 1-4 alkyl;X is selected from cyano, carboxyl or a derivative thereof, 5-tetrazolyl and alkylsulfonylcarbamyl having a Ci-6 alkyl moiety thereof; and n is 0 or an integer selected from 1, 2, 3, 4, 5 and 6.

[0057] To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.EXAMPLES

[0058] The anti-tumor activity of plinabulin as a single agent compared to coadministration with talazoparib was evaluated in a MDA-MB-231 human breast cancer xenograft model in Athymic nude mice.

[0059] Plinabulin was provided as a 4 mg / mL solution in 40% Solutol, 60% Propylene Glycol. Prior to use, this solution was diluted with D5W and gently mixed to achieve a clear solution at a concentration of 0.75 mg / mL to deliver a dose of 7.5 mg / kg in a 10 mL / kg dosing volume.

[0060] Talazoparib was provided as a crystalline solid. Prior to dosing, an appropriate amount of Talazoparib solid was weighed out and dissolved in DMA followed by sequential additions of Kolliphor (Solutol) HS 15 and PBS to a concentration of 0.0165 mg / mL in final ratio of 10% DMA, 5% Kolliphor (Solutol) HS, and 85% PBS. Talazoparib was dosed as a clear solution at a concentration of 0.0165 mg / mL to deliver a dose of 0.165 mg / kg in a 10 mL / kg dosing volume.

[0061] The vehicle control was 8% Kolliphor (Solutol) HS 15, 12% Propylene Glycol, and 80% D5W, formulated fresh prior to each dose. The vehicle control was dosed intraperitoneally at a 10 mL / kg dose volume.

[0062] The MDA-MB-231 human breast tumor cell line was maintained in RPML1640 with 5% FBS and 1% Penicillin / Streptomycin. Cells were housed in a 5% CO2 atmosphere. The cultures were expanded in tissue culture flasks at a 1 :5 split ratio until asufficient number of cells were harvested. Cells were harvested using a 0.25% trypsin / EDTA mixture.

[0063] Female Athymic nude (Crl:NU(NCr)-Foxnlnu) mice were received at 5 weeks of age. All mice were acclimated for at least 5-7 days prior to study initiation. The mice were housed in microisolator cages and maintained under specific pathogen-free conditions. The mice were fed Teklad Global Diet 2920x irradiated laboratory animal diet and autoclaved water was freely available. DietGel 76A was provided as needed for supplemental nutrition.

[0064] Female mice were inoculated under isoflurane anesthesia in the right inguinal mammary fat pad with 0.1 mL of a 50% RPMI-1640 / 50% Matrigel mixture containing a suspension of IxlO7cells / mouse of live MDA-MB-231 tumor cells. At time of inoculation, the mice were 6 weeks old.

[0065] Tumor bearing animals were monitored and tumors were measured periodically until they reached designated start size. Twenty-eight days following inoculation, forty mice with tumor sizes of 76-128 mm3were randomized into four groups of ten mice, each with a mean of 96 mm3. Tumor volumes and body weights were recorded when the mice were randomized and were taken twice weekly thereafter. Clinical observations were made daily. Dosing was performed via intraperitoneal injection for Vehicle Control and Plinabulin and administered via oral gavage for Talazoparib as described below in Table 1. Talazoparib BID dosing was administered eight hours apart. Plinabulin was administered one hour post morning dose of Talazoparib on combined dosing days.Table 1. Study Groupings*Plinabulin was administered 1 hour post the morning (AM) dose of Talazoparib on combined dosing days.ABID doses were administered approximately 8 hours apart.

[0066] Mice were euthanized as they reached individual tumor volume endpoint of greater than or equal to 1,500 mm3. The study was ended on Day 60 and all remaining mice that did not reach tumor volume endpoint were euthanized as long-term survivors.

[0067] At individual mouse endpoint or study end (Day 60), mice were euthanized and tumors were excised. Wet weights of the tumors were recorded, and tissues were then discarded.

[0068] Mean TGI was calculated for Day 33 (final day all mice were on study) utilizing the following formula. All mice were included in the TGI calculations.

[0069] All statistical analyses in the xenograft study were performed with GraphPad Prism software. / ? < 0.05 was considered statistically significant.

[0070] Differences in Day 33, 43, and 51 tumor volumes and percent change in body weight values were confirmed using a one-way ANOVA, unpaired, parametric with the Tukey’s Multiple Comparison test. A two-tailed Student’s t-test with Welch’s correction was also used to verify any differences between each group and the vehicle control, as well as single agents and their respective combination groups.

[0071] Increase in survival fractions were confirmed by the log rank test with a comparison of each treatment group to the Vehicle Control group. All animals that reached individual tumor volume endpoint or were sacrificed as LTS were included in the statistical analyses. These data were used to calculate mean and median survival and perform log rank comparisons for each group. For statistical analysis purposes, any mouse sacrificed as LTS was assigned a death day of Day 60.

[0072] The Vehicle Control group [Group 1] resulted in a mean tumor volume of 1004.7 mm3on Day 33. This group resulted in a median survival of 42 days (Min: 33, Max: 60). Nine of ten mice were sacrificed upon reaching individual tumor volume endpoint. Theremaining mouse was euthanized and noted as a long-term survivor on Day 60. Upon necropsy, this group resulted in a mean tumor wet weight of 1,136.5 mg (n=10) with a minimum individual tumor weight of 652 mg and maximum of 1,838 mg.

[0073] Treatment with Talazoparib 0.165 mg / kg [Group 2] resulted in a mean tumor volume of 405.7 mm3on Day 33. This group produced a TGI of 65.9% (n=10) when compared to the Vehicle Control group on Day 33. A statistically significant decrease in mean tumor volume was observed when compared to the Vehicle Control group on Days 33 and 43 (ANOVA and Student’s t-test; p<0.05). This group resulted in a median survival of 60 days (Min: 51, Max: 60). A statistically significant increase in survival was observed when compared to the Vehicle Control group. Four of ten mice were sacrificed upon reaching individual tumor volume endpoint. The remaining six mice were euthanized and noted as long-term survivors on Day 60. Upon necropsy, this group resulted in a mean tumor wet weight of 1,040.4 mg (n=10) with a minimum individual tumor weight of 591 mg and maximum of 1,703 mg.

[0074] Treatment with Plinabulin 7.5 mg / kg [Group 3] resulted in a mean tumor volume of 385.2 mm3on Day 33. This group produced a TGI of 68.2% (n=10) when compared to the Vehicle Control group on Day 33. A statistically significant decrease in mean tumor volume was observed when 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 when compared to single agent treatment with Talazoparib (Group 2). This group resulted in a median survival of 60 days (Min: 51, Max: 60). Two of ten mice were sacrificed upon reaching individual tumor volume endpoint. Mouse 3 was euthanized on Day 46 due to a severely distended abdomen. The remaining seven mice were euthanized and noted as long-term survivors on Day 60. Upon necropsy, this group resulted in a mean tumor wet weight of 721.9 mg (n=10) with a minimum individual tumor weight of 371 mg and maximum of 1,250 mg.

[0075] Treatment with Talazoparib 0.165 mg / kg + Plinabulin 7.5 mg / kg [Group 4] resulted in a mean tumor volume of 363.5 mm3on Day 33. This group produced a TGI of 70.6% (n=10) when compared to the Vehicle Control group on Day 33. A statistically significant decrease in mean tumor volume was observed when compared to the Vehicle Control group on Days 33, 43, 51, and 60 (ANOVA and Student’s t-test; p<0.05). Also, astatistically significant decrease in mean tumor volume was observed on Days 43 and 60 when compared to single agent treatment with Talazoparib (Group 2) (Student’s t-test; p<0.05); however, no significant difference in mean tumor volume was observed when compared to single agent treatment with Talazoparib (Group 2) on Days 33 and 51. Additionally, no significant difference in mean tumor volume was observed when compared to single agent treatment with Plinabulin (Group 3) on Days 33, 43, 51, and 60. This group resulted in a median survival of 60 days (Min: 60, Max: 60).

[0076] The effect the various treatments on mean tumor volume (with last tumor volume carried forward) is shown in Figure 1. Mean tumor wet weights obtained ex -vivo at time of termination are shown in Figure 2. Notably, the combination therapy (Group 4) resulted in the greatest efficacy with a TGI of 71% on Day 33. Single treatment with Talazoparib (Group 2) or Plinabulin (Group 3) produced TGIs of 66% and 68%, respectively, on Day 33.

[0077] Efficacy was also evaluated by tumor growth delay (survival) when compared to the Vehicle Control group. The effect of treatment on survival is shown in Figure 3, including only tumor related deaths. Treatment with Talazoparib (Group 2), Plinabulin (Group 3), and Talazoparib + Plinabulin (Group 4) all resulted in a median survival of 60 days; an increase of 18 days in median survival when compared to the Vehicle Control group. Talazoparib + Plinabulin (Group 4) distinctly resulted in no mice reaching tumor volume endpoint (>1,500 mm3) by Day 60.

[0078] These results demonstrate the improved efficacy of the combination of talazoparib and plinabulin. Without being bound to a single theory of operation, the combination in these types of drugs allows for complementary mechanisms of action to lead to a more effective suppression of tumor growth than either drug alone. In some embodiments, combinations according to the disclosure may leverage distinct mechanisms of the disclosed drugs to achieve a synergistic anti-cancer effect. For example, Plinabulin's interference with microtubule dynamics might potentiate the accumulation of DNA damage by simultaneously disrupting cell division, while PARP inhibitors might exacerbate the cell's inability to repair this damage. In some embodiments, this combination can result in increased DNA damage, leading to enhanced apoptosis (programmed cell death) of cancer cells. Furthermore, the combination of plinabulin, a PARP inhibitor, and optionally one ormore anti-cancer compounds, may assist in overcoming resistance to single-agent or double agent therapies. The combination of these therapies may also expand the therapeutic efficacy of one or more compounds of the disclosure across a wider range of cancers.

[0079] Fig. 4 shows the effect of different treatments on body weight change over time, and may be used as a proxy for assessing drug toxicity in animal studies. Group 1 is the vehicle control with a healthy increase in body weight, indicating the absence of drug- induced toxicity. Group 2, treated with Talazoparib, and Group 3, treated with Plinabulin, also show some increases in body weight relative to Group 1. Group 4, receiving the combination of Talazoparib and Plinabulin, also demonstrates increases in body weight. Despite the administration of two drugs, which could potentially have additive toxic effects leading to greater weight changes, this group's profile remains similar to the control group, indicating that the combination does not exacerbate the toxicity of either drug when used alone. This outcome could be counterintuitive as combining two agents might be expected to increase overall toxicity.

[0080] Accordingly, in some embodiments, the combination of Talazoparib and Plinabulin may reduce side effects commonly associated with PARP inhibitors like Talazoparib. Additionally, in some embodiments, the combination of Talazoparib and Plinabulin may reduce neutropenia, a common side effect of PARP inhibitor cancer treatments that results in reduced white blood cell counts.

[0081] Fig. 4 also suggests that a higher total amount of drugs can be administered without increased side effects since the combination therapy group maintains body weight similar to the control. Accordingly, in some embodiments, the disclosure provides for more flexible dosing regimens that achieve therapeutic efficacy without the corresponding increase in toxicity typically associated with higher total drug doses.

Claims

WHAT IS CLAIMED IS:

1. A method of treating cancer, comprising co-administering to a subject in need thereof plinabulin and a PARP inhibitor.

2. The method of claim 1, wherein plinabulin is administered intravenously.

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

4. The method of any one of claims 1-3, wherein 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.

5. The method of any one of claims 1-3, wherein 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.

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

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

8. The method of claim 6 or 7, wherein talazoparib is administered once per day.

9. The method of claim 6 or 7, wherein talazoparib is administered twice per day.

10. The method of any one of claims 1-9, wherein the dose of plinabulin administered is from 10 mg / m2to 40 mg / m2.11 . The method of any one of claims 1-9, wherein the dose of plinabulin administered is from 15 mg to 120 mg.

12. The method of claim 11, wherein the dose of plinabulin administered is about 40 mg.

13. The method of any one of claims 1-12, wherein plinabulin is administered once per week.

14. The method of any one of claims 1-12, wherein plinabulin is administered twice per week.

15. The method of any one of claims 1-12, wherein plinabulin is administered once every three weeks.

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

17. The pharmaceutical composition of claim 16, wherein 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.

18. The pharmaceutical composition of claim 16, wherein 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.

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

20. A kit, comprising: a first pharmaceutical composition comprising plinabulin or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a PARP inhibitor.

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

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