NK RECEPTOR ANTAGONISTS FOR CANCER PATIENTS
The present disclosure relates generally to a method of blocking, attenuating, or limiting the development of one or more vasomotor symptoms (VMS) in a patient who has cancer, has had cancer, or has an increased risk for cancer by administering a NK antagonist.
1 . A method of blocking, attenuating, or limiting the development of one or more vasomotor symptoms (VMS) in a patient who has cancer, has had cancer, or has an increased risk for cancer, wherein the patient will be undergoing hormone deprivation therapy, a medical and/or surgical procedure that may cause VMS, comprising administering an effective amount of a neurokinin receptor (NK) antagonist, for a time period prior to, and optionally concurrently with, the hormone deprivation therapy, a medical and/or surgical procedure.
2 . The method of claim 1 , wherein the neurokinin receptor antagonist is a neurokinin-3 receptor (NK3) antagonist.
3 . The method of claim 2 , wherein the neurokinin-3 receptor antagonist is selected from osanetant, fezolinetant, pavinetant, talnetant, (S)-3-methyl-2-phenyl-N-(1-phenylpropyl)-4-quinolinecarboxamide (SB-222,200), (−)-(R)—N-(α-methoxycarbonylbenzyl)-2-phenylquinoline-4-carboxamide (SB-218,795), 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c] [1,4]oxazin-8(1H)-yl]pyridin-3-yl}-N,2-dimethylpropanamide (NT-814), or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof.
4 . The method of claim 3 , wherein the neurokinin-3 receptor antagonist is osanetant or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof.
5 . The method of claim 4 , wherein the effective amount of osanetant is less than about 400 mg per day.
6 . The method of claim 5 , wherein the effective amount of osanetant is from about 10 to about 350 mg per day.
7 . The method of claim 5 , wherein the effective amount of osanetant is less than about 200 mg per day
8 . The method of claim 7 , wherein the effective amount of osanetant is from about 10 to about 150 mg per day.
9 . The method of claim 4 , wherein the effective amount of osanetant is about 300 mg per day.
10 . The method of claim 9 , wherein the osanetant is administered once a day.
11 . The method of claim 9 , wherein the osanetant is administered twice a day, each dose being about 150 mg.
12 . The method of any preceding claim, wherein hormone therapy for the patient is contraindicated.
13 . The method of claim 12 , wherein the hormone therapy is estrogen therapy.
14 . The method of claim 1 , wherein the hormone deprivation therapy is treatment with a selective estrogen receptor modulator (SERM).
15 . The method of claim 14 , wherein the SERM is tamoxifen.
16 . The method of claim 14 , wherein the patient is a female patient.
17 . The method of claim 14 , wherein the patient is a post-menopausal female patient.
18 . The method of claim 1 , wherein the hormone deprivation therapy is treatment with a gonadotropin-releasing hormone (GnRH) agonist or antagonist.
19 . The method of claim 18 , wherein the patient is a male patient.
20 . The method of claim 18 , wherein the GnRH agonist is leuprolide.
21 . The method of claim 1 , wherein the hormone deprivation therapy is treatment with a selective estrogen receptor degrader (SERD).
22 . The method of any preceding claim, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, or prostate cancer.
23 . The method of any preceding claim, wherein the cancer is hormone receptor-positive cancer.
24 . The method of any preceding claim, wherein the cancer is breast cancer.
25 . The method of any one of claims 1 - 13 , 18 - 20 , or 22 - 23 , wherein the cancer is prostate cancer.
26 . The method of any proceeding claim, wherein the patient has tested positive for a BRCA1, BRCA2 or PALB2 mutation.
27 . The method of any preceding claim, wherein the time period for administration of the NK antagonist prior to the hormone deprivation therapy, a medical and/or surgical procedure is about 12 weeks.
28 . The method of any preceding claim, wherein the time period over which the NK antagonist is administered prior to the hormone deprivation therapy, a medical and/or surgical procedure is about 8 weeks.
29 . The method of any preceding claim, wherein the time period over which the NK antagonist is administered prior to the hormone deprivation therapy, a medical and/or surgical procedure is about 4 weeks.
30 . The method of any preceding claim, wherein the time period over which the NK antagonist is administered prior to the hormone deprivation therapy, a medical and/or surgical procedure is about one week.
31 . The method of any preceding claim, wherein the patient continues to receive a NK antagonist after the hormone deprivation therapy, a medical and/or surgical procedure.
32 . The method of any preceding claim, wherein the NK antagonist is administered concurrently with hormone deprivation therapy, a medical and/or surgical procedure.
33 . The method of any one of the preceding claims, further comprising administering one or more of an additional therapeutic agent.
34 . The method of claim 33 , wherein the additional therapeutic agent is a selective estrogen receptor modulator (SERM).
35 . The method of claim 33 , wherein the SERM is tamoxifen.
36 . The method of claim 33 , wherein the additional therapeutic agent is a gonadotropin-releasing hormone (GnRH) agonist or antagonist.
37 . The method of claim 33 , wherein the GnRH agonist is leuprolide.
38 . The method of claim 33 , wherein the additional therapeutic agent is a nonsteroidal antiandrogen.
39 . The method of claim 33 , wherein the additional therapeutic agent is a kappa opioid agonist.
40 . The method of claim 33 , wherein the additional therapeutic agent is a SERD.
41 . A method of preventing hypertrophy of kisspeptin/neurokinin B/dynorphin (KNDy) neurons in a patient in need thereof by administering to said patient an effective amount of a NK antagonist.
42 . The method of claim 41 , wherein the NK antagonist is osanetant or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof.
43 . A method for reducing the frequency and severity of hormone deprivation therapy-induced vasomotor symptoms or surgery-induced vasomotor symptoms in a cancer patient, the method comprising administering a combination of a hormone antagonist and an NK antagonist to the cancer patient in need thereof, wherein the NK antagonist is administered twice a day, each dose comprising from about 100 mg to about 200 mg of the NK antagonist.
44 . The method of claim 43 , wherein the NK antagonist is a NK3 antagonist.
45 . The method of claim 44 , wherein the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof.
46 . The method of claim 43 , wherein the cancer patient is a BRCA1/2 positive breast cancer patient.
47 . The method of any one of claims 43 - 46 , wherein the NK antagonist is administered twice a day, each dose comprising about 150 mg of the NK antagonist
48 . A method for reducing the frequency and severity of tamoxifen-induced vasomotor symptoms or surgery-induced vasomotor symptoms in a cancer patient, the method comprising administering a combination of tamoxifen and an NK antagonist to the cancer patient in need thereof, wherein the NK antagonist is administered twice a day, each dose comprising from about 100 mg to about 200 mg of the NK antagonist.
49 . The method of claim 48 , wherein the NK antagonist is a NK3 antagonist.
50 . The method of claim 49 , wherein the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof.
51 . The method of claim 48 , wherein the cancer patient is a BRCA1/2 positive breast cancer patient.
52 . The method of any one of claims 48 - 51 , wherein the NK antagonist is administered twice a day, each dose comprising about 150 mg of the NK antagonist.
53 . A method for reducing leuprolide-induced vasomotor symptoms or surgery-induced vasomotor symptoms in a cancer patient, the method comprising administering a combination of leuprolide and an NK antagonist to the cancer patient in need thereof, wherein the NK antagonist is administered twice a day, each dose comprising from about 100 mg to about 200 mg of the NK antagonist.
54 . The method of claim 53 , wherein the NK antagonist is a NK3 antagonist.
55 . The method of claim 54 , wherein the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof.
56 . The method of claim 53 , wherein the cancer patient is a prostate cancer patient.
57 . The method of any one of claims 53 - 56 , wherein the NK antagonist is administered twice a day, each dose comprising about 150 mg of the NK antagonist.
58 . A method for reducing the frequency and severity of tamoxifen-induced vasomotor symptoms or surgery-induced vasomotor symptoms in a cancer patient, the method comprising administering a combination of tamoxifen and an NK antagonist to the cancer patient in need thereof, wherein the NK antagonist is administered twice a day, each dose comprising from about 25 mg to about 100 mg of the NK antagonist.
59 . The method of claim 58 , wherein the NK antagonist is a NK3 antagonist.
60 . The method of claim 59 , wherein the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof.
61 . The method of claim 58 , wherein the cancer patient is a BRCA1/2 positive breast cancer patient or a HR positive breast cancer patient.
62 . The method of any one of claims 58 - 61 , wherein the NK antagonist is administered twice a day, and the total daily dose of the NK antagonist ranges from about 50 mg per day to about 200 mg per day.
63 . The method of any one of claims 58 - 62 , wherein the NK antagonist is administered prior to initiation of tamoxifen treatment or prior to surgery for a period of less than one week.
64 . A method for reducing leuprolide-induced vasomotor symptoms or surgery-induced vasomotor symptoms in a cancer patient, the method comprising administering a combination of leuprolide and an NK antagonist to the cancer patient in need thereof, wherein the NK antagonist is administered twice a day, each dose comprising from about 25 mg to about 100 mg of the NK antagonist.
65 . The method of claim 64 , wherein the NK antagonist is a NK3 antagonist.
66 . The method of claim 65 , wherein the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof.
67 . The method of claim 64 , wherein the cancer patient is a prostate cancer patient.
68 . The method of any one of claims 64 - 67 , wherein the NK antagonist is administered twice a day, and the total daily dose of the NK antagonist ranges from about 50 mg per day to about 200 mg per day.
69 . The method of any one of claims 64 - 68 , wherein the NK antagonist is administered prior to initiation of leuprolide treatment or prior to surgery for a period of less than one week.
70 . A method for reducing the frequency and severity of vasomotor symptoms in a patient undergoing bilateral salpingo-oophorectomy, the method comprising administering an NK antagonist to the patient in need thereof, wherein the NK antagonist is administered twice a day, each dose comprising from about 25 mg to about 100 mg of the NK antagonist.
71 . The method of claim 70 , wherein the NK antagonist is a NK3 antagonist.
72 . The method of claim 71 , wherein the NK3 antagonist is osanetant, or a pharmaceutically acceptable salt thereof.
73 . The method of claim 70 , wherein the patient undergoing bilateral salpingo-oophorectomy is a breast cancer patient.
74 . The method of any one of claims 70 - 73 , wherein the NK antagonist is administered twice a day, and the total daily dose of the NK antagonist ranges from about 50 mg per day to about 200 mg per day.
75 . The method of any one of claims 70 - 74 , wherein the NK antagonist is administered prior to the bilateral salpingo-oophorectomy for a period of less than one week.
76 . The method of any one of claims 43 - 75 , wherein the patient continues to receive a NK antagonist after the hormone deprivation therapy, a medical and/or surgical procedure.
77 . The method of any one of claims 43 - 75 , wherein the NK antagonist is administered concurrently with hormone deprivation therapy, a medical and/or surgical procedure.
78 . The method of any one of claims 1 - 77 , wherein the method alleviates social isolation stress in the cancer patient.