Treatment of ovarian cancer with nirogacestat

Abstract

The present disclosure relates to methods for treating ovarian cancer comprising nirogacestat or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 267,413, filed February 1, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to a method for treating ovarian cancer, comprising administering nirogacestat or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment. [Background technology]

[0003] Ovarian granulosa cell tumors (OvGCTs) represent 5-7% of all ovarian cancers (approximately 1500-2000 new cases diagnosed per year in the United States (US)) and are the most common subtype (70%) of ovarian sex cord tumors. The mean age at diagnosis of OvGCTs is 50 years: 12% of OvGCT patients are under 30 years of age, and 57% are between 30 and 59 years of age. OvGCTs are usually slow growing and often do not lead to mortality, so the prevalence is high relative to the incidence. Median overall survival (OS) is approximately 13 years (range 11-15 years) from time of diagnosis, and 10-year OS has been shown to be 90%.

[0004] OvGCTs tend to recur after primary surgery and primary platinum-based therapy. Recurrence rates in case series ranged from 32% to 44% (the longest reported time to recurrence was 40 years). Median recurrence-free survival was 8.4 years (range 6.8-9.9 years).

[0005] OvGCTs are derived from early ovarian mesenchyme and are composed of granulosa cells, thecal cells, and fibroblasts.

[0006] Hyperestrogenism has been reported in patients with OvGCTs and is associated with tumor production of estrogens, anti-Müllerian hormone (AMH), and inhibins A and B. This hormone production distinguishes OvGCTs from serous ovarian cancer and may serve as a tumor-specific pharmacodynamic marker.

[0007] Currently, there is no US Food and Drug Administration (FDA) approved treatment for OvGCT. Surgery, in some cases, with adjuvant chemotherapy, is the mainstay of initial treatment. Adjuvant chemotherapy is typically with platinum-based regimens, i.e., paclitaxel-carboplatin, cyclophosphamide-cisplatin, or bleomycin-etoposide-cisplatin. Objective response rates (ORR) with any single agent therapy in the recurrent setting are low. Furthermore, combination therapy in the recurrent setting has failed to demonstrate improved progression-free survival (PFS) rates. Thus, there is an unmet need for agents with higher response rates and potential to improve PFS in this patient population. Summary of the Invention

[0008] Provided herein is a method for treating ovarian cancer, the method comprising administering to a patient in need of treatment about 50 mg to about 600 mg per day of nirogacestat, or a pharma- ceutically acceptable salt thereof.

[0009] Provided herein is a method for treating ovarian cancer, the method comprising administering to a patient in need of treatment for ovarian cancer a dosage form comprising about 10 mg to about 500 mg of nirogacestat, or a pharma- ceutically acceptable salt thereof.

[0010] Provided herein is a method for treating ovarian cancer, comprising administering to a patient in need of treatment about 10 mg to about 300 mg twice daily of nirogacestat or a pharma- ceutically acceptable salt thereof. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 100 mg / day. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 200 mg / day. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 300 mg / day.

[0011] In some embodiments, about 25 mg of nirogacestat or a pharmaceutically acceptable salt is administered at one time to a patient in need of ovarian cancer treatment. In some embodiments, about 50 mg of nirogacestat or a pharmaceutically acceptable salt is administered at one time to a patient in need of ovarian cancer treatment. In some embodiments, about 100 mg of nirogacestat or a pharmaceutically acceptable salt is administered at one time to a patient in need of ovarian cancer treatment.

[0012] In some embodiments, nirogacestat or a pharmaceutically acceptable salt thereof is administered at about 50 mg twice a day. In some embodiments, nirogacestat or a pharmaceutically acceptable salt thereof is administered at about 100 mg twice a day. In some embodiments, nirogacestat or a pharmaceutically acceptable salt thereof is administered at about 150 mg twice a day.

[0013] In some aspects, the ovarian cancer is an ovarian granulosa cell tumor. In some aspects, the patient exhibits hyperestrogenism.

[0014] In some embodiments, the pharma- ceutically acceptable salt form is a hydrobromide salt form. In some embodiments, the hydrobromide salt form is a dihydrobromide salt form.

[0015] In some embodiments, the patient is a human.

[0016] In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof is orally administered. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof is orally administered as a solid dosage form. In some embodiments, the solid dosage form is a tablet or a capsule. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] I. Definition To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0018] Generally, the nomenclature used herein and the laboratory procedures of organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0019] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as "one or more" and "at least one," may be used interchangeably herein. In certain aspects, the term "a" or "an" means "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple."

[0020] Furthermore, "and / or" as used herein should be interpreted as a specific disclosure of each of the two specified features or components, whether or not the other is present. Thus, the term "and / or" as used in phrases such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (single), and "B" (single). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0021] The term "nirogacestat" refers to the single enantiomer (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide.

[0022] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as, for example, a human subject.

[0023] As used herein, the terms "treat", "treated" and "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Thus, those in need of treatment include those already diagnosed with a disorder or suspected of having a disorder. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, whether detectable or undetectable; reduction in the extent of a condition, disorder, or disease; stabilization (i.e., not worsening) of a condition, disorder, or disease; delay in onset or slowing of progression of a condition, disorder, or disease; improvement or remission (partial or complete) of a condition, disorder, or disease state; improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or improvement or amelioration of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival in the absence of treatment. The term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound that is sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or clinician.

[0024] In certain embodiments, a subject is successfully "treated" for cancer, e.g., multiple myeloma, if, in accordance with the methods of the present invention, the patient exhibits one or more of the following: a reduction in the number or complete disappearance of cancer cells, a reduction in one or more symptoms associated with the particular cancer, a reduction in morbidity and mortality, an improvement in quality of life, progression-free survival ("PFS"), disease-free survival ("DFS"), overall survival ("OS"), metastasis-free survival ("MFS"), complete response ("CR"), minimal residual disease ("MRD"), partial response ("PR"), stable disease ("SD"), a reduction in progressive disease ("PD"), an increase in time to progression ("TTP"), or any combination thereof. In some embodiments, nationally or internationally accepted standards of treatment outcome for a given cancer can be used to determine whether a therapeutically effective amount of nirogacestat or a pharma- ceutically acceptable salt thereof meets any of these particular end points (e.g., CR, PFS, PR).

[0025] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation, and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0026] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of Compound A or Compound B. These salts can be prepared in situ during the manufacturing process of the administration vehicle or dosage form, or by separately reacting the purified compound of the present invention in its free base form with a suitable organic or inorganic acid and isolating the salt formed during subsequent purification. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J.Pharm.Sci.66:1-19).

[0027] Pharmaceutically acceptable salts of the subject compounds include, for example, conventional non-toxic salts or quaternary ammonium salts of the compounds derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and the like.

[0028] In certain embodiments, the compounds of the present invention may contain one or more acidic functional groups, and therefore can form pharma- ceutically acceptable salts with pharma-ceutically acceptable bases. The term "pharma-ceutically acceptable salts" in these examples refers to the relatively non-toxic inorganic and organic base addition salts of the compounds of the present invention. These salts can also be prepared in situ during the manufacturing process of the administration vehicle or dosage form, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharma-ceutically acceptable metal cation, with ammonia, or with a pharma-ceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, for example, Berge et al., supra).

[0029] The term "about" or "approximately" refers to the tolerance of a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0030] Unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are to be interpreted inclusively rather than exclusively, and are used with the express understanding that Applicant intends each of these terms to be so interpreted in interpreting this patent, including the claims which follow.

[0031] II. Treatment Methods Provided herein is a method for treating ovarian cancer, comprising administering to a patient in need of treatment about 50 mg to about 600 mg / day of nirogacestat or a pharma- ceutically acceptable salt thereof. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof is administered at a dose of about 50 mg to about 575 mg / day, about 75 mg to about 575 mg / day, about 100 mg to about 575 mg / day, about 125 mg to about 575 mg / day, about 150 mg to about 575 mg / day, about 175 mg to about 575 mg / day, about 200 mg to about 575 mg / day, about 225 mg to about 575 mg / day, about 250 mg to about 575 mg / day, about 275 mg to about 575 mg / day, or about 300 mg to about 575 mg / day. about 300 mg to about 575 mg / day, about 325 mg to about 575 mg / day, about 350 mg to about 575 mg / day, about 375 mg to about 575 mg / day, about 400 mg to about 575 mg / day, about 425 mg to about 575 mg / day, about 450 mg to about 575 mg / day, about 475 mg to about 575 mg / day, about 500 mg to about 575 mg / day, or about 525 mg to about 575 mg / day. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 50 mg / day, about 75 mg / day, about 100 mg / day, about 125 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, about 250 mg / day, about 275 mg / day, about 300 mg / day, about 325 mg / day, about 350 mg / day, about 375 mg / day, about 400 mg / day, about 425 mg / day, about 450 mg / day, about 475 mg / day, about 500 mg / day, about 525 mg / day, about 550 mg / day, about 575 mg / day, or about 600 mg / day.

[0032] Provided herein is a method for treating ovarian cancer, comprising administering to a patient in need of treatment for ovarian cancer a dosage form containing about 10 mg to about 500 mg of nirogacestat or a pharma- ceutically acceptable salt thereof. In some embodiments, the nirogacestat or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 mg to about 475 mg per administration, about 25 mg to about 475 mg per administration, about 50 mg to about 475 mg per administration, about 75 mg to about 475 mg per administration, about 100 mg to about 475 mg per administration, about 125 mg to about 475 mg per administration, about 150 mg to about 475 mg per administration, about 175 mg to about 475 mg per administration, about 250 mg to about 475 mg per administration, about 300 mg to about 475 mg per administration, about 400 mg to about 475 mg per administration, about 500 mg to about 475 mg per administration, about 600 mg to about 475 mg per administration, about 700 mg to about 475 mg per administration, about 800 mg to about 475 mg per administration, about 800 mg to about 475 mg per administration, about 900 mg to about 475 mg per administration, about 100 mg to about 475 mg per administration, about 125 mg to about 475 mg per administration, about 150 mg to about 475 mg per administration, about 175 mg to about 475 mg per administration, about 150 mg to about 475 mg per administration, about 180 mg to about 475 mg per administration, about 190 mg to about 475 mg per administration, about 200 mg to about 475 mg per administration, about 250 mg to about 475 mg per administration, about 300 mg 00 mg to about 475 mg in one dose, about 225 mg to about 475 mg in one dose, about 250 mg to about 475 mg in one dose, about 275 mg to about 475 mg in one dose, about 300 mg to about 475 mg in one dose, about 325 mg to about 475 mg in one dose, about 350 mg to about 475 mg in one dose, about 375 mg to about 475 mg in one dose, about 400 mg to about 475 mg in one dose, or about 425 mg to about 475 mg in one dose. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 10 mg per dose, about 25 mg per dose, about 50 mg per dose, about 75 mg per dose, about 100 mg per dose, about 125 mg per dose, about 150 mg per dose, about 175 mg per dose, about 200 mg per dose, about 225 mg per dose, about 250 mg per dose, about 275 mg per dose, about 300 mg per dose, about 325 mg per dose, about 350 mg per dose, about 375 mg per dose, about 400 mg per dose, about 425 mg per dose, about 450 mg per dose, about 475 mg per dose, or about 500 mg per dose.

[0033] Provided herein is a method for treating ovarian cancer, comprising administering to a patient in need of treatment about 10 mg to about 300 mg of nirogacestat or a pharma- ceutically acceptable salt thereof twice daily. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 10 mg to about 275 mg twice daily, about 25 mg to about 275 mg twice daily, about 50 mg to about 275 mg twice daily, about 75 mg to about 275 mg twice daily, about 100 mg to about 275 mg twice daily, about 125 mg to about 275 mg twice daily, about 150 mg to about 275 mg twice daily, about 175 mg to about 275 mg twice daily, about 200 mg to about 275 mg twice daily, or about 225 mg to about 275 mg twice daily. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 10 mg twice daily, about 25 mg twice daily, about 50 mg twice daily, about 75 mg twice daily, about 100 mg twice daily, about 125 mg twice daily, about 150 mg twice daily, about 175 mg twice daily, about 200 mg twice daily, about 225 mg twice daily, about 250 mg twice daily, about 275 mg twice daily, or about 300 mg twice daily.

[0034] In some embodiments, the pharma- ceutically acceptable salt form is a hydrobromide salt form. In some embodiments, the hydrobromide salt form is a dihydrobromide salt form.

[0035] Provided herein is a method for treating ovarian cancer, comprising administering to a patient in need of treatment about 50 mg to about 600 mg per day of nirogacestat dihydrobromide. In some embodiments, the nirogacestat dihydrobromide is administered at a dose of about 50 mg to about 575 mg per day, about 75 mg to about 575 mg per day, about 100 mg to about 575 mg per day, about 125 mg to about 575 mg per day, about 150 mg to about 575 mg per day, about 175 mg to about 575 mg per day, about 200 mg to about 575 mg per day, about 225 mg to about 575 mg per day, about 250 mg to about 575 mg per day, about 275 mg to about 575 mg per day, or about 280 mg to about 575 mg per day. 575 mg / day, about 300 mg to about 575 mg / day, about 325 mg to about 575 mg / day, about 350 mg to about 575 mg / day, about 375 mg to about 575 mg / day, about 400 mg to about 575 mg / day, about 425 mg to about 575 mg / day, about 450 mg to about 575 mg / day, about 475 mg to about 575 mg / day, about 500 mg to about 575 mg / day, or about 525 mg to about 575 mg / day. In some embodiments, nirogacestat dihydrobromide is administered at about 50 mg / day, about 75 mg / day, about 100 mg / day, about 125 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, about 250 mg / day, about 275 mg / day, about 300 mg / day, about 325 mg / day, about 350 mg / day, about 375 mg / day, about 400 mg / day, about 425 mg / day, about 450 mg / day, about 475 mg / day, about 500 mg / day, about 525 mg / day, about 550 mg / day, about 575 mg / day, or about 600 mg / day.

[0036] Provided herein is a method for treating ovarian cancer, comprising administering to a patient in need of treatment for ovarian cancer a dosage form containing about 10 mg to about 500 mg of nirogacestat dihydrobromide. In some embodiments, the nirogacestat dihydrobromide is administered in an amount of about 10 mg to about 475 mg, about 25 mg to about 475 mg, about 50 mg to about 475 mg, about 75 mg to about 475 mg, about 100 mg to about 475 mg, about 125 mg to about 475 mg, about 150 mg to about 475 mg, about 175 mg to about 475 mg, or about 200 mg. about 225 mg to about 475 mg in one dose, about 250 mg to about 475 mg in one dose, about 275 mg to about 475 mg in one dose, about 300 mg to about 475 mg in one dose, about 325 mg to about 475 mg in one dose, about 350 mg to about 475 mg in one dose, about 375 mg to about 475 mg in one dose, about 400 mg to about 475 mg in one dose, or about 425 mg to about 475 mg in one dose. In some embodiments, nirogacestat dihydrobromide is administered at about 10 mg per dose, about 25 mg per dose, about 50 mg per dose, about 75 mg per dose, about 100 mg per dose, about 125 mg per dose, about 150 mg per dose, about 175 mg per dose, about 200 mg per dose, about 225 mg per dose, about 250 mg per dose, about 275 mg per dose, about 300 mg per dose, about 325 mg per dose, about 350 mg per dose, about 375 mg per dose, about 400 mg per dose, about 425 mg per dose, about 450 mg per dose, about 475 mg per dose, or about 500 mg per dose.

[0037] Provided herein is a method for treating ovarian cancer, comprising administering to a patient in need of treatment about 10 mg to about 300 mg of nirogacestat dihydrobromide twice daily. In some embodiments, nirogacestat dihydrobromide is administered at about 10 mg to about 275 mg twice daily, about 25 mg to about 275 mg twice daily, about 50 mg to about 275 mg twice daily, about 75 mg to about 275 mg twice daily, about 100 mg to about 275 mg twice daily, about 125 mg to about 275 mg twice daily, about 150 mg to about 275 mg twice daily, about 175 mg to about 275 mg twice daily, about 200 mg to about 275 mg twice daily, or about 225 mg to about 275 mg twice daily. In some embodiments, nirogacestat or dihydrobromide is administered at about 10 mg twice daily, about 25 mg twice daily, about 50 mg twice daily, about 75 mg twice daily, about 100 mg twice daily, about 125 mg twice daily, about 150 mg twice daily, about 175 mg twice daily, about 200 mg twice daily, about 225 mg twice daily, about 250 mg twice daily, about 275 mg twice daily, or about 300 mg twice daily.

[0038] In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof (e.g., dihydrobromide form) is administered once, twice, three times, or four times a day. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof (e.g., dihydrobromide form) is administered twice a day. When nirogacestat or a pharma- ceutically acceptable salt thereof (e.g., dihydrobromide form) is administered multiple times a day, the daily dose administered each time may be the same or different. For example, when a total daily dose of about 300 mg of nirogacestat or a pharma- ceutically acceptable salt thereof (e.g., dihydrobromide form) is administered twice a day, the patient may be administered two doses of 150 mg (e.g., one dose of 150 mg at 8 a.m. and one dose of 150 mg at 8 p.m.), or may be administered a dose of 100 mg in the morning and a dose of 200 mg in the evening. Each dose may consist of multiple solid dosage forms, for example, an individual dose of 150 mg (i.e., a morning dose of a total daily dose of 300 mg administered in two divided doses) may be administered as three 50 mg tablets.

[0039] In some aspects, the ovarian cancer is an ovarian granulosa cell tumor. In some aspects, the patient exhibits hyperestrogenism.

[0040] In some embodiments, the patient is a human. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof (e.g., dihydrobromide form) is orally administered. In some embodiments, nirogacestat or a pharma- ceutically acceptable salt thereof (e.g., dihydrobromide form) is orally administered as a solid dosage form. In some embodiments, the solid dosage form is a tablet or capsule. In some embodiments, the solid dosage form is a tablet.

[0041] Working Example Example 1: Phase 2 Study of Nirogacestat in Adult Patients with Recurrent / Refractory Ovarian Granulosa Cell Tumors (OvGCT) General Design: A multicenter, single-arm, phase 2, open-label treatment study will be conducted to determine the efficacy, safety, tolerability, and pharmacokinetics of nirogacestat in adult participants with relapsed / refractory OvGCT. Participants must have received at least one course of prior systemic therapy for OvGCT and have measurable disease by RECISTv1.1 to meet eligibility criteria.

[0042] Participants will be screened up to 28 days prior to their first dose of study treatment (nirogacestat), and full participation will be based on inclusion and exclusion criteria.

[0043] Eligible participants will be enrolled into the study using an Interactive Response Technology (IRT) system after a pre-all-dose baseline assessment on Cycle 1 Day 1 (C1D1). After C1D1, participants will attend the clinic for scheduled study visits monthly for the first year and then every 3 months until the end of study participation.

[0044] Participants who prematurely discontinue study treatment for any reason are required to attend the clinic for an End of Treatment (EOT) visit within 7 days after the investigator's decision to no longer use study treatment, and then return for a Safety Follow-Up (FUP) visit 30 days (+7 days) after the last dose of study treatment.

[0045] Based on current enrollment assumptions, the estimated trial duration is 5 years, with all participants followed for at least 2 years (unless the trial is stopped early due to futility).

[0046] Number of participants: Approximately 43 people.

[0047] Treatment Arms and Duration: At C1D1, participants will be enrolled into the study using the IRT system and will receive study treatment (nirogacestat, 3x50mg tablets) at 150mg (orally) twice daily (BID) in continuous 28-day cycles.

[0048] Participants will continue on study treatment until death, disease progression, discontinuation of study treatment for any reason, termination of the study by the sponsor for any reason, or until the participant becomes eligible for expanded access by the sponsor.

[0049] The objectives and endpoints are shown in Table 1. [Table 1] [Table 2]

[0050] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In the event that a term in this application is found to be defined differently in a document incorporated herein by reference, the definition provided herein shall serve as the definition of that term.

[0051] While the invention has been described in relation to specific embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is generally intended to cover any variations, uses, or adaptations in accordance with the principles of the present disclosure, including such departures from the present disclosure that are within known or customary practice in the art to which this invention pertains, as may be applied to the essential features described above and fall within the scope of the appended claims.

[0052] In addition to the various embodiments described herein, the present disclosure includes the following embodiments, numbered E1 through E22. This list of embodiments is presented as an exemplary list, and the application is not limited to these embodiments.

[0053] E1. A method for treating ovarian cancer, comprising administering to a patient in need of treatment about 50 mg to about 600 mg per day of nirogacestat, or a pharma- ceutically acceptable salt thereof.

[0054] E2. A method for treating ovarian cancer, comprising administering to a patient in need of treatment for ovarian cancer a dosage form comprising about 10 mg to about 500 mg of nirogacestat or a pharma- ceutically acceptable salt thereof.

[0055] E3. A method for treating ovarian cancer, comprising administering to a patient in need of treatment for ovarian cancer about 10 mg to about 300 mg twice daily of nirogacestat or a pharma- ceutically acceptable salt thereof.

[0056] E4. The method of any one of E1-E3, wherein said nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 100 mg / day.

[0057] E5. The method of any one of E1-E3, wherein said nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 200 mg / day.

[0058] E6. The method of any one of E1-E3, wherein said nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 300 mg / day.

[0059] E7. The method of any one of E1-E6, wherein about 25 mg of nirogacestat or a pharma- ceutically acceptable salt thereof is administered at one time to said patient in need of treatment for ovarian cancer.

[0060] E8. The method of any one of E1-E6, wherein about 50 mg of nirogacestat or a pharma- ceutically acceptable salt thereof is administered at one time to said patient in need of treatment for ovarian cancer.

[0061] E9. The method of any one of E1-E6, wherein about 100 mg of nirogacestat or a pharma- ceutically acceptable salt thereof is administered at one time to said patient in need of treatment for ovarian cancer.

[0062] E10. The method of any one of E1-E9, wherein said nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 50 mg, twice daily.

[0063] E11. The method of any one of E1-E9, wherein said nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 100 mg, twice daily.

[0064] E12. The method of any one of E1-E9, wherein said nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 150 mg, twice daily.

[0065] E13. The method of any one of E1-E2 and E4-E9, wherein said nirogacestat or a pharma- ceutically acceptable salt thereof is administered once, twice, three times, or four times daily.

[0066] E14. The method of E13, wherein said nirogacestat or a pharma- ceutically acceptable salt thereof is administered twice daily.

[0067] E15. The method according to any one of E1-E14, wherein said ovarian cancer is an ovarian granulosa cell tumor.

[0068] E16. The method according to any one of E1 to E15, wherein said patient exhibits hyperestrogenism.

[0069] E17. The method of any one of E1-E16, wherein said pharma-ceutically acceptable salt form is a hydrobromide salt form.

[0070] E18. The method of E17, wherein said hydrobromide salt form is a dihydrobromide salt form.

[0071] E19. The method of any one of E1-E18, wherein said patient is a human.

[0072] E20. The method according to any one of E1 to E19, wherein said nirogacestat or a pharma- ceutically acceptable salt thereof is administered orally.

[0073] E21. The method of E20, wherein said nirogacestat or a pharma- ceutically acceptable salt thereof is administered orally in a solid dosage form.

[0074] E22. The method of E21, wherein said solid dosage form is a tablet or a capsule.

Claims

1. 1. A method for treating ovarian cancer, comprising administering to a patient in need of such treatment about 50 mg to about 600 mg per day of nirogacestat, or a pharma- ceutically acceptable salt thereof.

2. 1. A method for treating ovarian cancer, comprising administering to a patient in need of such treatment a dosage form comprising from about 10 mg to about 500 mg of nirogacestat or a pharma- ceutically acceptable salt thereof.

3. 1. A method for treating ovarian cancer, comprising administering to a patient in need of such treatment about 10 mg to about 300 mg twice daily of nirogacestat or a pharma- ceutically acceptable salt thereof.

4. The method of any one of claims 1 to 3, wherein the nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 100 mg / day.

5. The method of any one of claims 1 to 3, wherein the nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 200 mg / day.

6. The method of any one of claims 1 to 3, wherein the nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 300 mg / day.

7. 7. The method of any one of claims 1 to 6, wherein about 25 mg of nirogacestat or a pharma- ceutically acceptable salt thereof is administered at one time to a patient in need of said treatment for ovarian cancer.

8. 7. The method of any one of claims 1 to 6, wherein about 50 mg of nirogacestat or a pharma- ceutically acceptable salt thereof is administered at one time to a patient in need of said treatment for ovarian cancer.

9. 7. The method of any one of claims 1 to 6, wherein about 100 mg of nirogacestat or a pharma- ceutically acceptable salt thereof is administered at one time to a patient in need of said treatment for ovarian cancer.

10. 10. The method of any one of claims 1 to 9, wherein the nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 50 mg, twice daily.

11. 10. The method of any one of claims 1 to 9, wherein the nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 100 mg, twice daily.

12. 10. The method of any one of claims 1 to 9, wherein the nirogacestat or a pharma- ceutically acceptable salt thereof is administered at about 150 mg, twice daily.

13. 10. The method of any one of claims 1-2 and 4-9, wherein the nirogacestat or a pharma- ceutically acceptable salt thereof is administered once, twice, three times, or four times daily.

14. 14. The method of claim 13, wherein the nirogacestat or a pharma- ceutically acceptable salt thereof is administered twice daily.

15. The method of any one of claims 1 to 14, wherein the ovarian cancer is an ovarian granulosa cell tumor.

16. The method of any one of claims 1 to 15, wherein the patient exhibits hyperestrogenism.

17. The method of any one of claims 1 to 16, wherein the pharma- ceutically acceptable salt form is a hydrobromide salt form.

18. 18. The method of claim 17, wherein the hydrobromide salt form is a dihydrobromide salt form.

19. The method of any one of claims 1 to 18, wherein the patient is a human.

20. The method according to any one of claims 1 to 19, wherein the nirogacestat or a pharma- ceutically acceptable salt thereof is administered orally.

21. 21. The method of claim 20, wherein the nirogacestat or a pharma- ceutically acceptable salt thereof is orally administered in a solid dosage form.

22. 22. The method of claim 21, wherein the solid dosage form is a tablet or a capsule.

Images