WO2019110688A1 - Composition comprenant du dégarélix pour une utilisation dans le traitement du cancer du sein - Google Patents

Composition comprenant du dégarélix pour une utilisation dans le traitement du cancer du sein Download PDF

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WO2019110688A1
WO2019110688A1 PCT/EP2018/083694 EP2018083694W WO2019110688A1 WO 2019110688 A1 WO2019110688 A1 WO 2019110688A1 EP 2018083694 W EP2018083694 W EP 2018083694W WO 2019110688 A1 WO2019110688 A1 WO 2019110688A1
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treatment
degarelix
day
breast cancer
composition
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PCT/EP2018/083694
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English (en)
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Tine Kold Olesen
Aron GOLDHIRSCH
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Ferring B.V.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to compositions comprising degarelix for use in the treatment of breast cancer, for example hormone responsive (also hormone-sensitive or hormone-dependent) breast cancer.
  • the degarelix may be particularly useful in the treatment of patients who are not responsive to GnRH agonist (e.g. triptorelin) therapy.
  • Breast cancer is cancer that develops from, or in, breast tissue. There are many kinds of breast cancer. Some breast cancers are dependent on specific hormones to continue growing or spreading.
  • Estrogen and progesterone are hormones which are produced by the ovaries of premenopausal women, and by some other tissues in both premenopausal and postmenopausal women and men.
  • the hormone estrogen stimulates the development and maintenance of female sex
  • Progesterone is involved in the menstrual cycle and pregnancy.
  • Estrogen and progesterone also promote the growth of some breast cancers, which are called hormone responsive, hormone-sensitive, or hormone-dependent breast cancers. These cancers may be identified by the presence of estrogen receptors and progesterone receptors on the tumour surface. The receptors become activated when hormones bind to them.
  • Activated receptors change the expression of specific genes, which may stimulate cell growth.
  • Cancers which include estrogen receptors on the surface may be referred to as estrogen receptor positive (also ER positive), while cancers which include progesterone receptors may be referred to as progesterone receptor positive (also PR or PgR positive). Cancers which include estrogen and/or progesterone receptors may also be referred to as hormone receptor positive. Approximately 80% of breast cancers are ER positive.
  • Hormone-dependent breast cancers may be treated by, for example, preventing the body from producing estrogen and/or progesterone, or by interfering with effects of estrogen and/or progesterone on breast cancer cells. Such treatments may slow or stop the growth of hormone-sensitive tumors, and may be referred to as hormone therapy.
  • the body may be prevented from producing estrogen and/or progesterone by blocking ovarian function. This may be referred to as ovarian ablation. Ovarian ablation may be effected by removal of the ovaries
  • Ovarian ablation using medication is also known.
  • One strategy is to inhibit the action of aromatase, the enzyme used to make estrogen.
  • Aromatase inhibitors are known as aromatase inhibitors. These are generally used in postmenopausal women because the ovaries in premenopausal women produce too much aromatase for the inhibitors to block effectively. Aromatase inhibitors may be used in premenopausal women if, for example, they are given together with a drug that suppresses ovarian function. Anastrozole (Arimidex®) and Letrozole (Femara®) are approved by the FDA and temporarily inactivate aromatase. Another aromatase inhibitor approved by the FDA is exemestane (Aromasin®), which permanently inactivates aromatase.
  • GnRFI agonists also known as Luteinising Flomnone Releasing Flomnone agonists, LFIRFI
  • GnRFI agonists interfere with the signals from the pituitary which stimulate the ovaries to produce estrogen, thereby halting estrogen production, and suppressing ovarian function.
  • GnRFI agonists include goserelin (Zoladex®) and leuprolide (Lupron®), which have been approved by the FDA for ovarian suppression.
  • GnRFI agonist is triptorelin (decapeptyl). Trials of triptorelin with exemestane have shown, however, that at least 17% of patients on hormone therapy with exemestane and triptorelin have sub- optimal estrogen suppression at any given time point. This is indicative that a certain group of patients is not responsive to GnRFI agonist (triptorelin) therapy for breast cancer.
  • GnRFI antagonists act in a different way to GnRFI agonists, competitively and reversibly binding to GnRFI receptors in the pituitary gland and therefore blocking release of LH and FSH.
  • Degarelix is a GnRH antagonist which is approved for the treatment of prostate cancer (see, e.g., EP 1003774, U.S. 5,925,730, U.S. 6,214,798, EP 02749000.2 and U.S.S.N. 12/155,897 and EP 08250703.9, the contents of which are hereby
  • degarelix is highly effective in the treatment of hormone responsive breast cancer.
  • degarelix may induce faster ovarian suppression than GnRH agonists.
  • the GnRH antagonist degarelix maintained consistent ovarian function suppression (OFS) for a longer treatment period than the GnRH agonist (triptorelin). This suggests activity in patients who are not responsive to GnRH agonist therapy or develop resistance to GnRH agonist therapy (whether as a monotherapy or in combination with a second therapy such as an aromatase inhibitor).
  • OFS ovarian function suppression
  • composition comprising degarelix for use in the treatment of (e.g. hormone- responsive) breast cancer in a subject who is not responsive to GnRH agonist therapy.
  • a subject who is not responsive to GnRH agonist therapy means a subject who does not achieve ovarian function suppression when treated with a GnRH agonist and/or a subject who does not maintain ovarian function suppression when treated with a GnRH agonist.
  • ovarian function suppression means that the subject has a serum estradiol level which is below post menopausal level (for example below 20 pg/mL, for example below 10 pg/mL, for example below 2.72 pg/mL, for example below 2.18 pg/mL).
  • the terminology“does not achieve(s) ovarian function suppression when treated with a GnRH agonist” means that the subject’s serum estradiol level does not decrease to below post menopausal level when treated with a GnRH agonist (for example does not decrease to below post menopausal level within 29 days of
  • commencement of treatment with a GnRH agonist for example does not decrease to below 2.72 pg/mL when treated with a GnRH agonist, for example does not decrease to below 2.72 pg/mL within 29 days of commencement of treatment with a GnRH agonist.
  • the terminology “does not maintain ovarian function suppression when treated with a GnRH agonist” means that the subject’s serum estradiol level is not maintained at below post menopausal level when treated with a GnRH agonist [for example is not maintained at below post menopausal level from day 29 of treatment to at least day 141 (e.g. at least day 180, e.g. at least 9 months, e.g.
  • At least 12 months, e.g. at least up to 2 years) of treatment with GnRH agonist for example not maintained at below 2.72 pg/mL when treated with a GnRH agonist, for example not maintained at 2.72 pg/mL from day 29 of treatment to at least day 141 (e.g. at least day 180, e.g. at least 9 months, e.g. at least 12 months, e.g. at least up to 2 years) of treatment with GnRH agonist].
  • a subject who is not responsive to GnRH agonist therapy may mean a subject who is completely unresponsive to GnRH agonist therapy (and who does not achieve ovarian function suppression when treated with a GnRH agonist), or a subject who later becomes either consistently or periodically unresponsive/resistant to GnRH agonist therapy (and who does not maintain ovarian function suppression when treated with a GnRH agonist).
  • the breast cancer is hormone-responsive breast cancer.
  • the subject is a female subject.
  • the subject is premenopausal.
  • the composition may be for administration at an initial dose of degarelix of 160 to 320 mg; and at a maintenance dose of degarelix of 60 to 160 mg, once every 20 to 36 days thereafter.
  • the composition may be for administration at an initial dose of degarelix of about 240 mg; and at a maintenance dose of about 80 mg degarelix once every approximately 28 days of treatment.
  • the composition is for co-administration with an aromatase inhibitor (e.g. letrozole).
  • an aromatase inhibitor e.g. letrozole
  • the composition may be for use prior to surgical treatment of breast cancer (neoadjuvant therapy).
  • the composition may be for use after surgical treatment of breast cancer (adjuvant therapy).
  • the composition is for treatment of hormone- responsive breast cancer for over six months (for example at least 168 days, for example at least 190 days, for example at least 200 days, for example at least 365 days).
  • the treatment maintains ovarian function
  • suppression for over six months for example at least 168 days, for example at least 190 days, for example at least 200 days, for example at least 365 days).
  • the term“maintains ovarian function suppression” means that the subject’s serum estradiol level is maintained at below post menopausal level when treated with a GnRH agonist [for example is maintained at below post menopausal level from day 29 of treatment to at least day 141 (e.g. at least day 180, e.g. at least 9 months, e.g. at least 12 months, e.g. at least up to 2 years) of treatment with GnRH agonist, for example is maintained at below 2.72 pg/mL when treated with a GnRH agonist, for example is maintained at 2.72 pg/mL from day 29 of treatment to at least day 141 (e.g.
  • Day 29 of treatment is the day by when ovarian function suppression should have been achieved if hormone therapy is to be effective.
  • the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 168 of treatment. More preferably, the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 190 of treatment. More preferably, the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 200 of treatment. More preferably, the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 365 of treatment.
  • degarelix may induce faster ovarian suppression than GnRH agonists. Further, and surprisingly, the applicants found that the GnRH antagonist degarelix maintained ovarian function suppression (OFS) for a longer treatment period than a GnRH agonist (triptorelin), the latter showing breakthroughs in estradiol (E2) levels which are indicative of ovarian function and treatment failure as early as 57 days after commencement of treatment (see Example 1 ). Overall the results suggest activity in patients who are not responsive to GnRH agonist therapy.
  • a composition comprising degarelix for use in the treatment of (e.g. hormone- responsive) breast cancer in a subject, wherein the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 168 of treatment.
  • the breast cancer is hormone-responsive breast cancer.
  • the subject is a female subject.
  • the subject is premenopausal.
  • the composition may be for use in the treatment of (e.g. hormone-responsive) breast cancer in a subject who is not responsive to GnRH agonist therapy.
  • the composition may be for administration at an initial dose of degarelix of 160 to 320 mg; and at a maintenance dose of degarelix of 60 to 160 mg, once every 20 to 36 days thereafter.
  • the composition may be for administration at an initial dose of degarelix of about 240 mg; and at a maintenance dose of about 80 mg degarelix once every approximately 28 days of treatment.
  • the composition is for co-administration with an aromatase inhibitor (e.g. letrozole).
  • an aromatase inhibitor e.g. letrozole
  • the composition may be for use prior to surgical treatment of breast cancer (neoadjuvant therapy).
  • the composition may be for use after surgical treatment of breast cancer (adjuvant therapy).
  • the composition is for treatment of hormone- responsive breast cancer for over six months (for example at least 168 days, for example at least 190 days, for example at least 200 days, for example at least 365 days).
  • the treatment maintains ovarian function
  • suppression for over six months for example at least 168 days, for example at least 190 days, for example at least 200 days, for example at least 365 days).
  • the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 168 of treatment.
  • the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 190 of treatment.
  • the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 200 of treatment.
  • the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 365 of treatment.
  • composition comprising degarelix for use in the treatment of (e.g. hormone- responsive) breast cancer in a subject, wherein the composition is for co- administration with an aromatase inhibitor.
  • the breast cancer is hormone-responsive breast cancer.
  • the subject is a female subject.
  • the subject is premenopausal.
  • the composition may be for use in the treatment of (e.g. hormone-responsive) breast cancer in a subject who is not responsive to GnRH agonist therapy.
  • the composition may be for administration at an initial dose of degarelix of 160 to 320 mg; and at a maintenance dose of degarelix of 60 to 160 mg, once every 20 to 36 days thereafter.
  • the composition may be for administration at an initial dose of degarelix of about 240 mg; and at a maintenance dose of about 80 mg degarelix once every approximately 28 days of treatment.
  • the composition may be for use prior to surgical treatment of breast cancer (neoadjuvant therapy).
  • the composition may be for use after surgical treatment of breast cancer (adjuvant therapy).
  • the composition is for treatment of hormone- responsive breast cancer for over six months (for example at least 168 days, for example at least 190 days, for example at least 200 days, for example at least 365 days).
  • the treatment maintains ovarian function
  • suppression from for over six months for example at least 168 days, for example at least 190 days, for example at least 200 days, for example at least 365 days).
  • the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 190 of treatment. More preferably, the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 200 of treatment. More preferably, the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 365 of treatment.
  • a method of treatment of (e.g. hormone-responsive) breast cancer in a subject who is not responsive to GnRH agonist therapy including a step of administering to a patient in need thereof a pharmaceutically effective amount of degarelix.
  • the breast cancer is hormone-responsive breast cancer.
  • the subject is a female subject.
  • the subject is premenopausal.
  • the degarelix may be administered at an initial dose of degarelix of 160 to 320 mg; and at a maintenance dose of degarelix of 60 to 160 mg, once every 20 to 36 days thereafter.
  • the composition may be administered at an initial dose of degarelix of about 240 mg; and at a maintenance dose of about 80 mg degarelix once every approximately 28 days of treatment.
  • the degarelix is co-administered with an aromatase inhibitor (e.g. letrozole).
  • an aromatase inhibitor e.g. letrozole
  • the method may be prior to surgical treatment of breast cancer (neoadjuvant therapy).
  • the method may be after surgical treatment of breast cancer (adjuvant therapy).
  • the method is for treatment of hormone-responsive breast cancer for over six months (for example at least 168 days, for example at least 190 days, for example at least 200 days, for example at least 365 days).
  • the treatment maintains ovarian function
  • suppression from for over six months for example at least 168 days, for example at least 190 days, for example at least 200 days, for example at least 365 days).
  • the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 190 of treatment. More preferably, the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 200 of treatment. More preferably, the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 365 of treatment.
  • a method of treatment of (e.g. hormone-responsive) breast cancer in a subject including a step of administering to a patient in need thereof a pharmaceutically effective amount of degarelix, wherein the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 168 of treatment.
  • the breast cancer is hormone-responsive breast cancer.
  • the subject is a female subject.
  • the subject is premenopausal.
  • the degarelix may be administered at an initial dose of degarelix of 160 to 320 mg; and at a maintenance dose of degarelix of 60 to 160 mg, once every 20 to 36 days thereafter.
  • the composition may be administered at an initial dose of degarelix of about 240 mg; and at a maintenance dose of about 80 mg degarelix once every approximately 28 days of treatment.
  • the degarelix is co-administered with an aromatase inhibitor (e.g. letrozole).
  • an aromatase inhibitor e.g. letrozole
  • the method may be prior to surgical treatment of breast cancer (neoadjuvant therapy).
  • the method may be after surgical treatment of breast cancer (adjuvant therapy).
  • the method is for treatment of hormone-responsive breast cancer for over six months (for example at least 168 days, for example at least 190 days, for example at least 200 days, for example at least 365 days).
  • the treatment maintains ovarian function
  • suppression from for over six months for example at least 168 days, for example at least 190 days, for example at least 200 days, for example at least 365 days).
  • the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 190 of treatment. More preferably, the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 200 of treatment. More preferably, the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 365 of treatment.
  • degarelix for, or in the manufacture of a medicament for, the treatment of (e.g. hormone-responsive) breast cancer in a subject who is not responsive to GnRH agonist therapy.
  • degarelix for, or in the manufacture of a medicament for, the treatment of (e.g. hormone-responsive) breast cancer wherein the treatment maintains a serum estradiol level below 2.72 pg/mL from day 29 of treatment to at least day 168 of treatment.
  • Figure 1 illustrates the design of the phase II trial described in Example 1 below. Premenopausal breast cancer patents were stratified (age ⁇ 39 vs 40+) and randomized. Arm A of the trial received Triptorelin +
  • hormone responsive breast cancer refers to breast cancer which is affected (e.g. promoted) by hormones such as estrogen and progesterone.
  • the invention provides use of a composition comprising degarelix GnRH antagonist for treating breast cancer in a subject, and related methods of treatment.
  • the disclosure of the invention has been exemplified by data obtained from clinical studies, in particular the TREND study with ClinicalTrials.Gov Identifier NCT02005887.
  • Degarelix is a potent GnRH antagonist that is an analog of the GnRH decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly -NH2) incorporating p-ureido-phenylalanines at positions 5 and 6 (Jiang et al. (2001 ) J. Med. Chem. 44:453-67).
  • Degarelix is a selective GnRH receptor antagonist (blocker) that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of gonadotrophins and consequently testosterone (T). Unlike GnRH agonists, GnRH receptor blockers do not induce a luteinizing hormone (LH) surge.
  • LH luteinizing hormone
  • the active ingredient degarelix is a synthetic linear
  • decapeptide amide containing seven unnatural amino acids, five of which are D-amino acids.
  • the drug substance is an acetate salt, but the active moiety of the substance is degarelix as the free base.
  • the acetate salt of degarelix is a white to off-white amorphous powder of low density as obtained after lyophilisation.
  • the chemical structure of degarelix has been previously shown (EP 1003774, US 5,925,730, U.S. 6,214,798) and may be represented by the formula:
  • Degarelix may be formulated for administration subcutaneously or intramuscularly (as opposed to intravenously), generally in the abdominal region, as described in further detail below.
  • the injection site may vary periodically to adapt the treatment to injection site discomfort.
  • injections should be given in areas where the patient will not be exposed to pressure, e.g. not close to waistband or belt and not close to the ribs.
  • degarelix by subcutaneous or intramuscular injection works well, but daily injections are generally not acceptable and so a depot formulation of degarelix may be utilized as describe in further detail in WO 03/006049 and U.S. Pub. Nos. 20050245455 and 20040038903. Briefly, administration of degarelix may be conducted using a depot technology in which the peptide is released from a biodegradable polymer matrix over a period of (typically) one to three months.
  • Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogues. Degarelix and these related GnRH antagonists are capable of forming a gel after injection, and this gel can act as a depot from which the peptide is released over a period of weeks or even months.
  • a key variable for formation of an effective degarelix depot is the concentration of the solution in combination with the amount of substance administered per se. The concentration must be within a functional range. If the formulation is too dilute then no depot is formed and the long duration of action is lost, regardless of the amount of drug substance given. If the formulation is too concentrated then gel formation will occur before the drug can be administered (e.g., with a syringe). Effective depot-forming
  • formulations of degarelix generally have a concentration of not less than 5 mg/mL degarelix, e.g. 5 to 40 mg/mL of degarelix.
  • degarelix may be provided as a powder for reconstitution (with a solvent) as solution for injection (e.g., subcutaneous injection, e.g., to form a depot as described above).
  • the powder may be provided as a lyophilisate containing degarelix (e.g. as acetate) and mannitol.
  • a suitable solvent is water (e.g., water for injection, or WFI).
  • degarelix may be provided in a vial containing 120 mg degarelix (acetate) for reconstitution with 3 ml_ WFI such that each ml_ of solution contains about 40 mg degarelix.
  • degarelix may be provided in a vial containing 80 mg degarelix (acetate). After reconstitution with about 4 ml_ (e.g., 4.2 ml_) WFI, each ml_ solution contains about 20 mg degarelix.
  • a preferred dosing regimen for treating adult females with breast cancer is a single 240 mg starting dose of degarelix administered as two subcutaneous injections of 120 mg; and followed by monthly maintenance doses of 80 mg of degarelix administered as a single subcutaneous injection beginning approximately 28 days or one month after the initial starting dose.
  • the dosing regimen for degarelix may be administered as an initial, starting dose of 240 mg administered as 2 injections of 3 ml_ of about 40 mg/mL degarelix formulation, followed by monthly maintenance doses of 80 mg administered as a single injection of 4 ml_ of about 20 mg/mL degarelix formulation.
  • monthly maintenance doses of 160 mg may be utilized, e.g., by administering 4 mL of about 40 mg/mL degarelix every month.
  • the reconstituted composition should be a clear liquid, free of undissolved matter.
  • LH luteinizing hormone
  • FSH follicle stimulating hormone
  • degarelix is effective in achieving and maintaining a serum estradiol level below 3 pg/mL from day 29 of treatment to at least day 168 of treatment. This is indicative of maintenance of long term ovarian function suppression.
  • NCT02005887 is a randomized phase II trial that was conducted to
  • Time to optimal ovarian function suppression [ Time Frame: up to 24 weeks ] This means the time from the first injection of Degarelix or Triptorelin to the first assessment of centrally assessed 17- -estradiol (E2) level in the range of optimal ovarian function suppression ( ⁇ 2.72 pg/mL or ⁇ 10 pmol/L) during the 6 cycles of neoadjuvant treatments.
  • E2 17- -estradiol
  • Ki67 proliferation marker changes [ Time Frame: Before day1 of cycle 1 and surgery ]
  • PRS patient-reported symptoms
  • FACT-ES Functional Assessment of Cancer Therapy Endocrine Subscale
  • FACT-ES Functional Assessment of Cancer Therapy Endocrine Subscale
  • FACTIT Functional Assessment of Chronic Illness Therapy
  • Stratification was performed according to age (in years) less than or equal to 39 versus 40 or more.
  • Estradiol (E2) levels were determined centrally from samples taken at day 1 of the first treatment cycle before the administration of the first dose of Degarelix or Triptorelin (baseline), and thereafter at 24 and 72 hours, 7 days and 14 days after the first injection, and on day 1 of cycles 2 to 6 before the administration of Degarelix or Triptorelin.
  • E2 ⁇ 2.72 pg/mL or ⁇ 10 pmol/L were 30% within 2 weeks, 60% within 4 weeks and 75% within 8 weeks, and that Degarelix provided more rapid suppression (i.e., 60% within 2 weeks, 95% within 4 weeks and 100% within 8 weeks).
  • Enrollment of 25 patients in each treatment arm provided at least 90% power to detect a difference in time to optimal ovarian function suppression between the two groups, using a two sample log-rank test with a two-sided significance level of 0.05. Randomized patients who received at least one injection of Triptorelin or Degarelix were included in the primary analysis. The primary endpoint was compared between the two treatment arms using a stratified two-sample log- rank test, with age as stratification factor.
  • the distribution of the primary endpoint was summarized using the method of Kaplan-Meier and the two- sided 95% confidence interval (Cl) for the difference in proportion of patients who achieve optimal ovarian function suppression between the two treatment arms at the end of the 1 st, 2nd and 4th cycle was provided.
  • PEPI Preoperative Endocrine Prognostic Index
  • the primary endpoint for patient-reported symptoms (PRS) analysis is the total PRS score measured at baseline, day 1 of cycle 2 and day 1 of cycle 4 of Triptorelin or Degarelix administration, and prior to surgery.
  • PRS patient-reported symptoms
  • the differences in PRS measurements between the two treatment arms over time were explored using the repeated measures analysis based on generalized estimating equation (GEE) model.
  • GEE generalized estimating equation
  • NCT02005887 (IBCSG 41-13; EudraCT Number: 2012-005326-29) is an interventional phase 2 study. Its allocation is randomized. Parallel
  • Arm A Triptorelin 3.75 mg i.m. on day 1 every 28 days for 6 cycles + Letrozole 2.5 mg/day orally for 6 cycles
  • Arm B Degarelix 240 mg s.c. on day 1 of cycle 1 , followed by 80 mg s.c. on day 1 of cycles 2 to 6 + Letrozole 2.5 mg every day orally for 6 cycles
  • the sex eligible for this study was female. Patients had to be 18 years and older (Adult, Senior). This study did not accept healthy volunteers.
  • Estradiol (E2) must be above 54 pg/mL (or above 198 pmol/L)
  • Hematopoietic status Absolute neutrophil count > 1.5 c 109/L, platelet count > 100 x 109/L, hemoglobin > 9 g/dL
  • premenopausal status was determined locally with 17-b- estradiol (E2) levels >54 pg/ml (or >198 pmol/l ), measured within 14 days prior to randomization. Definitive surgery was performed within 2-3 weeks after the last administration of Triptorelin or Degarelix.
  • the primary objective of this study was to identify the time to optimal ovarian function suppression (Time frame up to 24 weeks).
  • Degarelix allowed faster optimal OFS than Triptorelin, and maintained optimal OFS throughout the neoadjuvant treatment period.
  • Figure 2 compares the estradiol E2 (pg/mL) profile for Triptorelin + Letrozole (T+L) in Figure 2A with the estradiol E2 (pg/mL) profile for Degarelix +
  • the Hazard ration (HR) with a 95% confidence interval (Cl) was 1 for T + L and 3.05 (1.65 - 5.65) for D + L.
  • the difference between the 14 day optimal OFS rate for T + L and D+L was significant (Log-rank p-value ⁇ 0.001 ).
  • Table I demonstrates that the primary endpoint time to optimal OFS was significantly faster among patients assigned with Degarelix + Letrozole (D+L) versus Triptorelin + Letrozole (T+L).
  • Degarelix maintained optimal OFS throughout the neoadjuvant treatment period as demonstrated by the E2 profile.
  • Figure 3 compares the estradiol E2 (pg/mL) profile for Triptorelin + Letrozole (T+L) in Figure 3A with the estradiol E2 (pg/mL) profile for Degarelix +
  • Degarelix maintained optimal OFS at 57, 85, 113 and/or 141 days. Degarelix maintained optimal OFS at least 141 days.
  • Table II below shows that the best overall response rate in patients receiving T + L was 46% compared with 44% in patients receiving D + L.
  • the absolute difference (90% Cl) was -2% (-25, 21 ).
  • the node negative rate at surgery in patients receiving T + L was 34.6% compared with 43.5 in patients receiving D + L.
  • the absolute difference (90% Cl) was 8.9 (-14.3,31.8).
  • the breast- conserving surgery (BCS) rate at surgery in patients receiving T + L was 42.3% compared with 52.2 in patients receiving D + L.
  • the absolute difference (90% Cl) was 10% (-13.5, 33.3).
  • Table II demonstrates that in patients receiving Degarelix and Letrozole, the best overall response rate is reduced. Table II also demonstrates that in patients receiving Degarelix, the node negative rate at surgery and the breast-conserving surgery (BCS) rate is increased.
  • Table III shows the most common adverse events according to treatment. Arthraligia was reduced in patients receiving D + L (32%) compared with patients receiving T + L (54%). Moreover, two patients assigned T + L had grade 3 AEs, hypertension and anemia.
  • Table III demonstrates that Degarelix is well-tolerated in patients.
  • Degarelix allowed faster optimal OFS than Triptorelin, and maintained optimal OFS throughout the neoadjuvant treatment period.
  • FIG. 3A shows the estradiol E2 (pg/mL) profile for Triptorelin + Letrozole (T+L).
  • Figure 3B shows the estradiol E2 (pg/mL) profile for Degarelix + Letrozole (D+L). Again, the dashed lines represents the cut-off for defining optimal OFS. It can be seen that, in stark contrast to the T+L group, no patient in the group receiving Degarelix + Letrozole (D+L) had sub- optimal OFS. In other words, in the patient group receiving Degarelix + Letrozole (D + L), optimal OFS was maintained for all patients, strongly suggesting that degarelix is effective in patients who are not responsive to GnRFI agonist therapy or develop resistance to GnRFI agonist therapy.
  • NCT02005887 showed zero non responders in the degarelix (D+L group) which is suggestive that there is a specific patient sub-population which is non-responsive to GnRFI agonist therapy but which does respond to degarelix treatment.

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Abstract

L'invention concerne le dégarélix pour le traitement du cancer du sein chez un sujet qui n'est pas sensible à une thérapie par agoniste de GnRH, également pour une co-administration avec un inhibiteur de l'aromatase.
PCT/EP2018/083694 2017-12-05 2018-12-05 Composition comprenant du dégarélix pour une utilisation dans le traitement du cancer du sein WO2019110688A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925730A (en) 1997-04-11 1999-07-20 Ferring Bv GnRH antagonists
WO2003006049A1 (fr) 2001-07-12 2003-01-23 Ferring Bv Antagonistes de l'hormone de liberation des gonadotrophines dans des concentrations permettant la gelification
WO2009037539A2 (fr) * 2007-09-17 2009-03-26 Preglem S.A. Traitement d'états pathologiques œstrogénodépendants chez des femmes pré-ménopausées

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Publication number Priority date Publication date Assignee Title
US5925730A (en) 1997-04-11 1999-07-20 Ferring Bv GnRH antagonists
EP1003774A1 (fr) 1997-04-11 2000-05-31 Ferring B.V. ANTAGONISTES DE GnRH MODIFIES AUX POSITIONS 5 ET 6
US6214798B1 (en) 1997-04-11 2001-04-10 Ferring Bv GnRH antagonists being modified in positions 5 and 6
WO2003006049A1 (fr) 2001-07-12 2003-01-23 Ferring Bv Antagonistes de l'hormone de liberation des gonadotrophines dans des concentrations permettant la gelification
US20040038903A1 (en) 2001-07-12 2004-02-26 Martin Luck Gonadotropin releasing hormone antagonists in gel-forming concentration
US20050245455A1 (en) 2001-07-12 2005-11-03 Martin Luck Gonadotropin releasing hormone antagonists in gel-forming concentrations
WO2009037539A2 (fr) * 2007-09-17 2009-03-26 Preglem S.A. Traitement d'états pathologiques œstrogénodépendants chez des femmes pré-ménopausées

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Title
DELLAPASQUA S ET AL: "TREND: A randomized phase II clinical trial evaluating the endocrine activity and efficacy of neoadjuvant degarelix versus triptorelin in premenopausal patients receiving letrozole for locally advanced endocrine responsive breast cancer (IBCSG 41-13)", CANCER RESEARCH, & 36TH ANNUAL SAN ANTONIO BREAST CANCER SYMPOSIUM; SAN ANTONIO, TX, USA; DECEMBER 10 -14, 2013, vol. 73, no. Suppl. 24, 1 December 2013 (2013-12-01), pages OT3 - 2, XP002780938 *
JIANG ET AL., J. MED. CHEM., vol. 44, 2001, pages 453 - 67
LAMBERTINI MATTEO ET AL: "Ovarian Function Suppression in Premenopausal Women with Early-Stage Breast Cancer", CURRENT TREATMENT OPTIONS IN ONCOLOGY MAY 2005, SPRINGER US, BOSTON, vol. 18, no. 1, 9 February 2017 (2017-02-09), pages 1 - 18, XP036184546, ISSN: 1527-2729, [retrieved on 20170209], DOI: 10.1007/S11864-017-0442-8 *
SPILKER: "Guide to Clinical Trials", 1991, RAVEN PRESS
SPILKER: "Quality of Life and Pharmacoeconomics in Clinical Trials Lippincott", 1996, RAVEN PUBLISHERS

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