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CN-122028929-A - Dosing regimen of tivalia-TFA for the treatment of prostate cancer

CN122028929ACN 122028929 ACN122028929 ACN 122028929ACN-122028929-A

Abstract

The present invention relates to a dosing regimen for a tivalia-TFA composition for treating prostate cancer. The dosing regimen included loading doses of 360 mg SC and 180 mg IM of the tivalience-TFA composition, and a low maintenance dose of the tivalience-TFA composition (360 mg SC) every six weeks from day 28. Thus, the dosing regimen according to the present invention provides an improved dosing regimen wherein a castration of 95% or more is achieved over a 52 week treatment period with fewer side effects and adverse events, thereby providing an optimized response/side effect relationship.

Inventors

  • Carol MacLean
  • Steve Van Oos

Assignees

  • 安迪威有限公司

Dates

Publication Date
20260512
Application Date
20241016
Priority Date
20231018

Claims (14)

  1. 1. A tivalia-TFA composition for treating prostate cancer, wherein the composition is administered by a dosing regimen comprising a loading dose and at least one maintenance dose, and wherein the loading dose comprises Subcutaneous administration of a 360 mg tivalia-TFA composition, Intramuscular administration of 180 mg tivalia-TFA compositions, and Wherein subcutaneous administration and intramuscular administration are performed substantially simultaneously.
  2. 2. The tivalia-TFA composition for use according to claim 1, wherein the subcutaneous 360 mg tivalia-TFA and the intramuscular 180 mg tivalia-TFA loading dose is administered over a period of no more than 1 hour, even more preferably over a period of no more than 10 minutes, even more preferably over a period of no more than 5 minutes.
  3. 3. The tivalia-TFA composition for use according to claim 1 or 2, wherein the maintenance dose comprises subcutaneous administration of 360 mg of the tivalia-TFA composition.
  4. 4. A tivalia-TFA composition for use according to any preceding claim, wherein the first maintenance dose is administered 28 days after the loading dose.
  5. 5. The tivalia-TFA composition for use according to claim 4, wherein one or more second maintenance doses are administered once every six weeks starting from the day of administration of the first maintenance dose.
  6. 6. A tivallik-TFA composition for use according to any preceding claim, wherein the dosing regimen provides a castration of ≡95% over a treatment period of at least 26 weeks, preferably at least 52 weeks.
  7. 7. A tivalia-TFA composition for use according to any preceding claim, wherein the tivalia-TFA composition is a microcrystalline suspension.
  8. 8. The tivalia-TFA composition for use according to claim 7, wherein the microcrystalline suspension comprises from 2.0 mol to 2.8 mol TFA per mole of tivalia in the composition.
  9. 9. A tivalia-TFA composition for use according to any preceding claim, wherein the dosing regimen provides a plasma testosterone concentration in a male subject of less than 0.5 ng/mL at least 72 hours after administration of the loading dose, and wherein the plasma testosterone concentration is determined by liquid chromatography/mass spectrometry (LC-MS).
  10. 10. A tivalia-TFA composition for use according to claim 9, wherein a plasma testosterone concentration of less than about 0.5 ng/mL is maintained for a treatment period of at least 26 weeks, preferably at least 52 weeks.
  11. 11. A tivalia-TFA composition for use according to any preceding claim, wherein the dosing regimen comprises administration of an additional pharmaceutical substance, preferably selected from an anti-tumour agent, an adrenergic receptor antagonist and a5α -reductase inhibitor.
  12. 12. A pharmaceutical formulation for treating prostate cancer comprising the composition according to any one of claims 1-11.
  13. 13. Pharmaceutical formulation for use according to claim 12, wherein the formulation further comprises an isotonic agent, preferably selected from mannitol or polyols, such as sugar alcohols, and/or pharmaceutically acceptable excipients.
  14. 14. A kit for treating prostate cancer comprising the composition of any one of claims 1-11 or the pharmaceutical formulation of any one of claims 12-13, wherein the kit further comprises at least one syringe for administration of a tivorax-TFA composition.

Description

Dosing regimen of tivalia-TFA for the treatment of prostate cancer Technical Field The present invention relates to compositions comprising tivorax-TFA for use in the treatment of prostate cancer, and to dosing regimens for such treatment. Background Prostate cancer is the second most common cancer in men worldwide, accounting for 15% of established cancers in men. The choice of treatment depends on a variety of factors, such as the rate of cancer growth, whether metastasis has occurred, and most importantly, the associated benefits and side effects of the treatment employed. Proliferation of prostate cancer depends on androgens produced primarily in the testes, and thus treatment of advanced and/or metastatic prostate cancer typically involves Androgen Deprivation Therapy (ADT). This is typically accomplished using bilateral orchiectomy or by drug castration with administration of Luteinizing Hormone Releasing Hormone (LHRH) analogues or antagonists, both of which are effective in inhibiting testosterone production. Tivorax (Ac-D-Nal-D-pClPhe-D-Pal-Ser-Tyr-D-Hci-Leu-Lys (iPr) -Pro-D-Ala-NH 2) is a synthetic gonadotropin-releasing hormone antagonist (GnRH antagonist) and therefore competes with the endogenous neuro-hormone GnRH (also known as luteinizing hormone-releasing hormone, LHRH) for binding to its receptors in the anterior pituitary. By reducing or blocking the effects of GnRH, tivorin inhibits the anterior pituitary release of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). In men, FSH plays an important role in spermatogenesis, and LH stimulates the testes to produce testosterone. Thus, tivorax can be used in androgen deprivation therapy to treat prostate cancer. Although the use of androgen deprivation therapy has achieved considerable success in the treatment and management of prostate cancer, such therapy has been associated with acute and long-term side effects and/or adverse events such as hyperlipidemia, fatigue, hot flashes, ignition effects (FLARE EFFECT), osteoporosis, insulin resistance, cardiovascular disease, anemia and sexual dysfunction (SEIDENFELD et al, single agent androgen suppression therapy in men with advanced prostate cancer: systemic reviews and meta-analysis （Single-Therapy Androgen Suppression in Men with Advanced Prostate Cancer: A Systematic Review and Meta-Analysis）,Ann. Intern. Med. 2000; 132: 566-577）. In particular, cardiovascular disease has proven to be of significant importance in this regard, as cardiovascular disease is today the leading cause of death in men with prostate cancer. A recent meta-analysis (see Li Gu et al, gonadotrophin releasing hormone antagonists compared to the cardiovascular adverse effects of GnRH agonists on prostate cancer: system review and meta-analysis, （Adverse cardiovascular effect following gonadotropin-releasing hormone antagonist versus GnRH agonist for prostate cancer treatment: A systematic review and meta-analysis）,Front. Endocrinol.,2023, 31, sec. Cancer Endocrinology, volume 14-2023) concludes that prostate cancer patients treated with GnRH antagonists have lower incidence of cardiovascular events, cardiovascular death and myocardial infarction than patients treated with GnRH agonists. Therefore, gnRH antagonists (e.g., tivorax) are preferred for use in androgen deprivation therapy, but special care must be taken to ensure that any adverse side effects, such as cardiovascular disease, are reduced. Several different dosing regimens for the treatment of prostate cancer using relatively low doses of tivalproic acid are known. It is also known to administer tivalirike by intramuscular, subcutaneous, and by combined subcutaneous/intramuscular administration, see for example the applicant's international application WO2018138703. However, while the dosing regimen disclosed in WO2018138703 provides beneficial results for some patients, a significant number of patients either have not been castrated at all or have failed to maintain castration throughout the treatment period. Thus, the dosing regimen disclosed in WO2018138703 has proven to be less effective over a relatively long treatment period in prostate cancer patients. Thus, there remains a need for an optimized dosing regimen for the treatment of prostate cancer that provides an optimized dose-response relationship in which relatively low doses of tivalrun can be used to reduce side effects (adverse events) associated with GnRH antagonists while at the same time ensuring that the patient remains castrated throughout the treatment period. Disclosure of Invention Accordingly, a first aspect of the present invention is to provide a dosing regimen for a tivalia-TFA composition for the treatment of prostate cancer, particularly advanced prostate cancer, which provides fewer side effects/adverse effects than, for example, treatment with conventional GnRH agonists and GnRH antagonists. In a second aspect, the invention provides a regimen of a tivalia-TFA composition,