US 2016O166583A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0166583 A1 Zukiwski et al. (43) Pub. Date: Jun. 16, 2016
(54) ONAPRISTONE EXTENDED-RELEASE Publication Classification COMPOSITIONS AND METHODS (51) Int. Cl. (71) Applicant: ARNOTHERAPEUTICS, INC., A613 L/567 (2006.01) Flemington, NJ (US) A619/20 (2006.01) (52) U.S. Cl. (72) Inventors: Alexander Zukiwski, Clarksburg, MD CPC ...... A6 IK3I/567 (2013.01); A61 K9/20 (US); Stefan Proniuk, Austin, TX (US) (2013.01) (21) Appl. No.: 14/942,809 (57) ABSTRACT 1-1. Onapristone extended-release formulations and methods of (22) Filed: Nov. 16, 2015 administering onapristone extended-release formulations are O O provided. Onapristone extended-release formulations pro Related U.S. Application Data vide Sufficient therapeutic activity as compared to immediate (60) Provisional application No. 62/080,868, filed on Nov. release formulations with reduced potential for adverse side 17, 2014. effects. Patent Application Publication Jun. 16, 2016 Sheet 1 of 4 US 2016/O166583 A1
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ONAPRSTONE EXTENDED-RELEASE ONA does not allow the PR complex to bind to DNA, does not COMPOSITIONS AND METHODS or minimally modulates PR-mediated genes, and inhibits ligand-induced PR phosphorylation, in contrast to other anti PRIORITY CLAIM progestins Beck 1996; Alfhippe 2009. Preclinical activity has been shown in several models, including endometrial 0001. This application claims priority to U.S. Provisional cancer Mueller 2003 and the clinical anticancer activity of Patent Application Ser. No. 62/080,868, filed Nov. 17, 2014. ONA has been previously documented in patients with hor The above referenced application is incorporated herein by mone therapy-naive Robertson 1999 or tamoxifen-resistant reference as if restated in full. The above referenced applica Jonat 2002 breast cancer. tion and all references cited herein, including but not limited 0007 Transcriptionally activated PR (APR) can be to patents and patent applications, are incorporated by refer detected by observational evaluation of the subnuclear distri ence in their entirety. bution pattern using immunohistochemistry (IHC). Using this method, APR can be used as a potentially predictive IHC BACKGROUND biomarker in endometrioid cancer of the uterus. See U.S. Pat. 0002 Onapristone (ONA) is an anti-progestin drug and No. 9,046,534. APR detection is being developed as a com progesterone receptor antagonist which was originally devel panion diagnostic to identify patients more likely to respond oped for potential contraceptive use and the use in benign to ONA Bonneterre 2015. gynecological disorders such as the treatment of uterine lei 0008 Early clinical studies employing the original imme omyomas. However, onapristone has demonstrated Substan diate release (IR) formulation of ONA have shown that ONA tial activity in advanced breast cancer. It is thought that ONA is well-tolerated with the exception of abnormalities in liver binds to the progesterone receptor (PR), preventing the PR function tests (LFTs) Cameron 1996, Cameron 2003, Crox from binding to DNA and thereby inhibiting or eliminating atto 1994, Jonat 2002, Robertson 1999. Studies with the PR-induced DNA transcription. See, e.g., Klijn et al., Proges original IR formulation were discontinued due to these LFT terone antagonists and progesterone receptor modulation in abnormalities. Id. the treatment of breast cancer, Steroids, V. 65, pp. 825–830 0009 Previously, onapristone was provided to patients (2000); Jonat et al., The clinical efficacy of progesterone with cancer (e.g., breast, endometrial, others) in an immediate antagonists in breast cancer, Endocrine Therapy of Breast release formulation of 100 mg and provided QD (once per Cancer, pp. 117-124. day). Onapristone has also been given to patients in endocri 0003) Onapristone is a type I progesterone receptor (PR) nology studies, at immediate release doses of 1 and 10 mg antagonist, which prevents PR-induced DNA transcription. doses resulting in a dose-dependent effect of onapristone on Presence of transcriptionally activated PR (APR) in tissue Suppression of gonadotrophin (luteinizing hormone LH and samples from a cancer patient, measured using, for example, follicle-stimulating hormone IFSH) secretion. Cameron an immunohistochemistry companion diagnostic procedure, 2003. However, these studies used immediate release formu indicates Susceptibility to treatment with onapristone anti lations of onapristone of unknown purity. Importantly, these cancer activity. Onapristone anti-cancer activity is docu studies addressed the dose and formulation of onapristone mented in multiple pre-clinical models and clinical studies in suitable for potential contraceptive use rather than the dose patients with hormone therapy-naive or tamoxifen-resistant and formulation Suitable for treating a disease such as cancer. breast cancer. Despite promising activity in breast cancer 0010 What is needed is an improved formulation of models, the development of onapristone as an oncology drug onapristone which allow for a continuous Suppression of the was terminated due to liver function test abnormalities. See, PR and methods of administering the same resulting in Suf e.g., Robertson et al., Eur J Cancer. 35(2):214-8 (Feb. 1999). ficient bioavailability to provide clinical benefit to cancer 0004 Expression of the progesterone receptor (PR) has patients at doses which result in less toxicity than the previous been described in breast Mote 2000, Lange 2008, endome clinical experience with onapristone. trial Kim 2013, Mortel 1984), prostate Lange 2007, Bonkhoff 2001, ovarian Sieh 2013, and several other can SUMMARY cers Yin 2010, Ishibashi 2005, Blankenstein 2000. Anti 0011 Aspects described herein provide extended-release progestins have been shown to have an inhibitory effect on the pharmaceutical compositions comprising onapristone as the growth of different type of cancer cells, and antiprogestin active ingredient in an amount from about 2 mg to about 100 treatment has been studied in breast Jonat 2013, endome mg. The extended-release pharmaceutical compositions (also trial Thigpen 1999, prostate Taplin 2008 cancers and uter referred to herein as ER formulations) further comprise ine sarcomas Koivisto-Korander 2007. excipients suitable for the desired dosage form (e.g., tablet, 0005. The effects of progesterone are mediated by two capsule, etc.) and for delaying the release of the active ingre distinct nuclear receptor proteins, PRA and PRB, two tran dient. Scriptional isoforms of the single PR gene. In luminal epithe 0012. Further aspects provide onapristone ER formula lial cells of the normal breast and in normal endometrium, tions utilizing highly purified onapristone (e.g., at least about both PR isoforms are expressed and are required to mediate 98%). In another aspect, the ratio of onapristone to inactive the physiological effects of progestin ligands Mote 2002, excipients in the ER formulations is about 0.05 to about 5%. Arnett-Mansfield 2004. The two PR isoforms have both been 0013 Inafurther aspect, the AUC (area under the curve) of detected in malignant tissues, such as breast, endometrial, onapristone is at least about 1578 ngh/ml over about an 8-12 ovarian and prostate cancers Cottu 2015. hour period after administration of a 10 mg dose BID (i.e., 0006 ONA is a type I antiprogestin which prevents PR twice per day) to a patient. monomers from dimerizing, inhibits ligand-induced phos 0014 Inanother aspect, the Cmax (maximum plasma con phorylation, prevents association of the PR with its co-acti centration) of onapristone is at least about 240 ng/ml over vators, and thus prevents PR-mediated DNA transcription. about an 8-12 hour period after administration of a 10 mg US 2016/0166583 A1 Jun. 16, 2016 dose BID to a patient. In yet another aspect, a steady state tical compositions or drug formulations that do not have a plasma concentration of onapristone is achieved at about 8 mechanism for delaying the release of the active ingredient days following the initial dose of the extended release following administration of the formulation to a patient. onapristone pharmaceutical composition. In another aspect, Exemplary extended release formulations are provided, for the extended-release onapristone pharmaceutical composi example, in Table 4 herein. The terms “treat,” “prevent,” or tion comprises at least about 10 mg to about 50 mg of onapris similar terms, as used herein, do not necessarily mean 100% tOne. or complete treatment or prevention. Rather, these terms refer to various degrees of treatment or prevention of a particular BRIEF DESCRIPTION OF THE DRAWINGS disease (e.g., 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 0015 FIG. 1 shows the exemplary Cmax (maximum 20%, 10%. 5%, or 1%) as recognized in the art as being active ingredient concentration) levels per ONA dose level beneficial. The terms “treatment' or “prevention' also refer to (10 mg, 20 mg, 30 mg, 40 mg, 50 mg extended-release BID delaying onset of a disease for a period of time or delaying (twice per day) and 100 mg QD (once per day)); onset indefinitely. The term “treatment” or “treating refers to 0016 FIG. 2 shows the exemplary AUC (area under the administering a drug or treatment to a patient or prescribing a curve) per ONA dose level (10 mg, 20 mg, 30 mg, 40 mg, 50 drug to a patient where the patient or a third party (e.g., mg extended-release formulations BID (twice per day) and caretaker, family member, or healthcare professional) admin 100 mg QD (once per day)); isters the drug or treatment 0017 FIG.3 shows the exemplary accumulation of ONA 0022. One aspect provides an extended-release pharma over time per ONA dose level (10 mg, 20 mg. 30 mg, 40 mg. ceutical composition comprising onapristone wherein 50 mg extended-release formulations BID (twice per day) onapristone is present in an amount from about 2 mg to about and 100 mg QD (once per day)); and 50 mg. Onapristone can be provided, for example, in quanti 0018 FIGS. 4A and 4B show exemplary ONA plasma ties of 2 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 37.5 mg, and levels over time per dose levels for the extended-release for 50 mg in any suitable extended release formulation (e.g., mulations BID (FIG. 4A) and the 100 mg formulation QD. formulations of Table 4) multiple times per day (e.g., twice per day) or once per day. ER formulations can include excipi DETAILED DESCRIPTION ents that delay the dissolution of the tablet and the subsequent release of onapristone into the gastrointestinal track which 0019. Before describing several exemplary aspects then is absorbed into the bloodstream of a patient over time described herein, it is to be understood that the invention is thereby reducing the C concentration compared to an IR not limited to the details of construction or process steps set formulation. A similar release profile can beachieved through forth in the following description. The aspects described the use of an osmotic tablet or a tablet film coated with a herein are capable of being practiced or being carried out in polymer that results in an extended release profile of the various ways. tablet. 0020. In another aspectonapristone ER formulations com 0023. In another aspect, onapristone ER formulations can prise onapristone (ONA) ((8S, 11R,13R,14S,17S)-11-4- be provided in any suitable dosage form (e.g., tablet, capsule, (dimethylamino)phenyl-17-hydroxy-17-(3-hydroxypro etc.) with a total weight of active ingredients plus excipients pyl)-13-methyl-1,2,6,7,8,11,12,14,15, 16 ranging from about 50 mg to 400 mg. In another aspect, the decahydrocyclopentalaphenanthren-3-one), an anti tablet can be a matrix tablet, film coated tablet or osmotic progestin drug and progesterone receptor antagonist having pump. In yet another aspect, onapristone ER formulations can the following structure: be administered to a patient in need of treatment withonapris tone once per day, twice per day (BID), or more to achieve the desired dose of onapristone.
0024. Further aspects provide onapristone ER formula tions wherein the purity of the onapristone is at least about 98%. Without being bound by theory, it is believed that using a highly purified form of onapristone in part decreases the liver function test abnormalities resulting in clinical benefits for cancer patients at all doses. 0025 Inanother aspect, the ratio of onapristone to inactive excipients in the onapristone ER formulation is about 0.05 (e.g., Table 4) to about 5%. 0026. Further aspects provide ER formulations wherein 0021. In one aspect, ER formulations of onapristone are the AUC of onapristone following the administration of 10 provided. The term “extended release” refers to a pharmaceu mg of the onapristone ER formulation to a patient BID is at tical compositions or drug formulation that is administered to least about 1578 ngh/ml over about 8-12 hours. In one a patient and has a mechanism to delay the release an active aspect, the time period can vary by about plus or minus two ingredient (i.e., drug). For example, ER pharmaceutical com hours. positions include the active ingredient (e.g., onapristone) and 0027. Another aspect provides onapristone ER formula excipients that delay release of the active ingredient (e.g., tions where the Cmax of onapristone following the adminis hydroxypropyl methylcellulose, ethyl cellulose, Eudragit(R) tration of 10 mg of the onapristone ER formulation to a (Evonik Industries) Sustained release formulations (poly patient BID is at least about 240 ng/ml over about 8-12 hours. methacrylates), polyvinylpyrrolidone (PVP), carrageenan, In one aspect, the time period can vary by about plus or minus etc.). The term “immediate release' (IR) refers to pharmaceu two hours. US 2016/0166583 A1 Jun. 16, 2016
0028. Another aspect provides onapristone ER formula approximately 50% (FIG. 24). A later Tmax value for the ER tions where a steady state plasma concentration of onapris form results in somewhat lower dose-corrected Cmax values tone is achieved at about 8 days following the administration for the ER form compared to the IR form. Steady state is of the onapristone ER formulations to a patient twice a day attained before day 8 with a meant/2 of 7.5hrs. (BID). 0029. Further aspects provide methods of administering 0036 Table 1 compares descriptive statistics for the pri onapristone to a patient comprising administering anonapris mary onapristone pharmacokinetic exposure parameters fol tone ER formulation twice per day (BID) to a cancer patient, lowing single oral doses from 10 to 50 mg of extended-release where the onapristone ER formulation comprises of at least onapristone compared to that from 100mg immediate-release about 10 mg to about 50 mg of onapristone. In one aspect, the onapristone (Study ARN-AR 18-CT-101). Exposure follow ER formulation is administered once per day. In another ing ERonapristone appears later than that for IRonapristone, aspect, the onapristone in the onapristone ER formulation is consistent with extended release formulations. However, the at least about 98% pure. extended-release aspects are not reflected in the overall dura 0030. In one aspect, the onapristone administered to a tion of exposure. Although study size is Small, onapristone patient it at least about 98% pure. In yet another aspect, exposure generally increases in proportion to ERonapristone onapristone in the onapristone ER formulations can be pro dose. Exposure at 50 mg ER onapristone is approximately vided, for example, in quantities of 2 mg, 2.5 mg, 5 mg, 10 20-50% that of 100 mg IR onapristone depending on the mg, 20 mg, 25 mg, 37.5 mg, and 50 mg. formulation. Variability in these parameters is similar for both 0031. In yet another aspect, the onapristone ER formula formulations and across ER onapristone dose levels. tions can be administered twice per day (BID) to a human subject in need of treatment, where the onapristone ER for TABLE 1 mulation comprises of at least about 10 mg to about 50 mg of onapristone. In one aspect, the ER formulation is adminis Summary of PK results for 52 Patients From Study ARN-AR18-CT-101 tered once per day. In another aspect, the disorder is selected Form ER ER ER ER ER IR Dose (mg) 10 2O 30 40 50 100 from the group consisting of breast cancer, endometrial can l 12 12 6 10 6 6 cer, prostate cancer, ovarian, uterine endometrioid cancers, AUC (ng * h mL) and other types of cancer which express the PR. 0032. In another aspect, the onapristone ER formulation is Mean 1578 4228 4856 6833 8966 40800 administered to a human subject having a disorder capable of CV9% 75 94 19 65 53 51 treatment with onapristone wherein the the AUC of onapris C. (ng/mL) tone following the administration of 10 mg of the onapristone Mean 240 S86 767 870 1459 4296 ER formulation to a patient BID is at least about 1578 ngh/ CV9% 67 77 15 67 48 S4 ml over about 8-12 hours. In another aspect, the time period tna (hrs) can vary by about plus or minus two hours. Mean 3.4 3.8 3.8 5.2 2.5 1.3 0033. In another aspect, the onapristone ER formulation is CV9% 47 50 51 68 55 61 administered to a human Subject having a disorder capable of t12 (hrs) treatment with onapristone by administering an onapristone Mean 8.9 7.9 3.9 23.9 11.1 23.6 ER formulation to the subject twice per day (BID) where the CV9% 120 39 31 183 140 16S Cmax of onapristone in the human Subject is at least about 240 ng/ml over about 8-12 hours. In another aspect, the onapristone ER formulation is administered once per day. In 0037 PK results are available in 19 patients from a second yet another aspect, the time period can vary by about plus or study (ARN-AR 18-CT-102) and show linear dose relation minus two hours. ships for C and AUC (Table 2) following single oral doses 0034. In another aspect, anonapristone ER formulation is from 10 to 50 mg of extended-release onapristone. Confirm administered to a human Subject having a disorder capable of ing the ARN-AR 18-CT-101 study, the ER formulation treatment with onapristone twice per day (BID) where a appears to be performing according to the dose release speci steady state plasma concentration is achieved at about 8 days. fications with at of approximately 8 hours and a T of 0035 PK results for onapristone are available for 52 approximately 3-4 hours. Steady state is also achieved within patients from the a first study (ARN-AR18-CT-101) (Table 8 days in this study. Day 29 and 57 data indicate no evidence 1). Variability for onapristone PK is moderate and greater for of accumulation over time, once steady state is reached. the IR versus the ER formulation. Onapristone Cmax and Onapristone exposure generally increases less than propor AUC values for the ER form are proportional to administered tionally with the ER onapristone dose formulation. Variabil dose (FIGS. 1 and 2). Based on observed mean AUC values, ity in these parameters is similar across ER onapristone dose oral bioavailability for the ER versus the IR formulation is levels. TABLE 2 Summary of PK results for 19 Patients From Study ARN-AR18-CT-102 Onapristone ER twice-daily dose Parameter 10 mg 20 mg 30 mg 40 mg 50 mg mean (CV%) n = 5 n = 5 n = 3 n = 3 n = 3
ex 4.0 (43) 3.6 (46) 4.0 (50) 3.0 (88) 3.3 (35) Cna, ng/mL, 260 (51) 362 (41) 325 (62) 680 (14) 538 (44) US 2016/0166583 A1 Jun. 16, 2016
TABLE 2-continued Summary of PK results for 19 Patients From Study ARN-AR18-CT-102 Onapristone ER twice-daily dose Parameter 10 mg 20 mg 30 mg 40 mg 50 mg mean (CV%) n = 5 n = 5 n = 3 n = 3 n = 3 AUC ng/mL*h 7013 (53) 9745 (44) 14380 (18) 17300 (27) 23541 (39) CL, L?h 1.85 (48) 2.04 (31) 2.13 (18) 2.18 (10) 2.4 (46) t12, h 5.46 (63) 5.61 (30) 9.46 (44) 5.45 (55) 15.9 (53)
0038 FIGS. 1 and 2 show the results of an exemplary weeks (Table 3). The median progression free survival (PFS) comparison of the relative systemic onapristone exposure was 57.5 days (range 21-281). following single oral doses from 10 to 50 mg of extended 0042. In study ARN-AR18-CT-101, in 52 female patients release onapristone compared to that from 100 mg immedi with PR-positive solid tumors, 9/46 patients (20%) receiving ate-release onapristone (Study ARN-AR 18-CT-101). the onapristone ER formulation at doses from 10-50 mg BID Onapristone exposure, assessed by Cmax (FIG. 1) and AUC demonstrated clinical benefit, vs. 0/6 (0%) patients receiving (FIG. 2), increases linearly across the ER onapristone dose the 100 mg once-daily onapristone IR formulation. Clinical range and is lower than that for IRonapristone at all ER dose benefit responses, defined as RECIST 1.1 partial response or levels. Surprisingly, as disclosed herein, the ER onapristone stable disease for at least 24 weeks, were seen only in patients formulations provided clinical benefit to patients despite receiving ER. Of interest, 7/9 of the patients with clinical lower onapristone exposure. benefit (78%) received doses below the established 100mg IR 0039 FIG. 3 shows the results of an exemplary compari dose and the patient with a partial response was treated at the Son of the degree of onapristone accumulation following lowest ER dose level, 10 mg BID. twice-daily oral doses from 10 to 50 mg of extended-release 0043. With respect to ARN-AR18-CT-102, 2 of 21 onapristone compared to that from daily oral 100 mg imme patients with prostate cancer had SD after week 12. Median diate-release onapristone (Study ARN-AR 18-CT-101). duration of treatment was 8 weeks. Accumulation for the ER onapristone formulation given twice daily is measurably greater than that for IRonapristone EXAMPLES given daily. 0044) The following non-limiting examples illustrate 0040 FIGS. 4A and 4B show exemplary plasma onapris aspects described herein. Not every element described herein tone concentration-time profiles for individual subjects fol is required. Indeed, a person of skill in the art will find numer lowing single oral doses of 50 mg extended-release onapris ous additional uses of and variations to the methods described tone compared to that from 100 mg immediate-release herein, which the inventors intend to be limited only by the onapristone (Study ARN-AR18-CT-101). The profiles for ER claims. All references cited herein are incorporated by refer onapristone generally reach maximum concentrations more ence in their entirety. slowly than those for IRonapristone, Supporting the extended release of drug from the ER formulation. Concentrations at all Example 1 dose levels of ER onapristone are generally lower than those for 100 mg IRonapristone. Surprisingly, as disclosed herein, ERFormulations the ER onapristone formulations provided clinical benefit to patients despite lower onapristone exposure. 0045 TABLE 4 TABLE 3 Onapristone Extended-Release Formulations Efficacy In Study ARN-AR18-CT-101 Amount per tablet (ng % change Duration Tumortype Dose Response STL weeks Component 2.5 mg 5 mg 10 mg 20 mg Function Serous OC 10 PR -52 40 Onapristone 2.50 S.OO 1O.OO 20.00 Active Serous OC 50 SD -7 34 Lactose 10.25 2O.SO 41.00 82.00 Filler Granulosa OC 40 SD -24 24 monohydrate Granulosa OC 30 SD +5 32 Microcrystalline 10.25 2O.SO 41.00 82.00 Filler EC 30 SD -13 30+ cellulose EC 2O SD +5 32 Pregelatinized 10.00 2O.OO 40.00 80.00 Disintegrant BC 50 SD -7 32+ starch BC 2O SD NA 28 Hydroxypropyl 16...SO 33.00 66.00 132.00 Binder? BC 40 SD -10 24 methylcellulose modified release agent Colloidal silicon O.25 O.SO 1.00 2.00 Glidant 0041 Clinical benefit (PR (partial response or SD (stable dioxide disease) for >24 weeks) was observed in ovarian, breast and Magnesium stearate O.25 O.SO 1.00 2.00 Lubricant uterine endometrioid cancers using the onapristone ER for Tablet weight (mg) 50.00 100.00 200.00 400.00 mulation. One patient with serous ovarian cancer experienced a PR (32 week duration) and 8 patients had SD for at least 24 US 2016/0166583 A1 Jun. 16, 2016
0046 Table 4 provide exemplary onapristone extended 0061 The PR determination for inclusion purposes was release formulations. In one aspect, the tablets can be pro performed on archived tissue blocks in the pathology depart vided to a patient alone or in any desired combination to ment of each participating center. Central PR/APR evaluation achieve the desired dose. was planned, but retrospective relative to inclusion and treat ment. Example 2 0062 Key exclusion criteria included significantly impaired liver or kidney function, creatinine clearance lower Preparing Exemplary Onapristone ER Formulations than 60 mL/min, total bilirubin >upper limit of normal 0047 Onapristone extended-release formulations can be (ULN), alkaline phosphatase >ULN (or >2.5xULN with liver prepared by the following exemplary method: or >5xULN with bone metastases), ALT/AST >ULN (or >2.5xULN with liver metastases), QTcf >480 msec, chronic 0048 Step 1: De-lump onapristone drug substance by inflammatory liver condition, severe concomitant disease, milling or by passing through a wire screen followed by uncontrolled brain metastases, inadequate washout from pre further passing the resulting de-lumpedonapristone through a vious therapy, inability to swallow or absorb tablets, use of wire screen of appropriate mesh size (e.g., 425 or 710 inhibitors, inducers or substrates of CYP3A4, or use of microns). progestin-based hormone replacement therapy. 0049 Step 2: Screen the colloidal silicon dioxide and approximately half of the pregelatinized Starch separately Example 4 through a screen of appropriate mesh size (e.g., 425 or 710 microns) into a stainless Steel blending container. The previ Study Design and Treatment ously-screened onapristone drug Substance from Step 1 is added to this blend. 0063. The study was an open-label, multicenter, random 0050 Step 3: The mixture is blended and screened through ized, parallel-group, two part phase 1-2 study with phase I a screen of appropriate mesh size (e.g., 425 or 710 microns). part of the trial discussed herein. To determine the recom 0051 Step 4: The remaining pregelatinized starch is mended phase 2 dose (RP2D), patients enrolled in this phase screened through a screen of appropriate mesh size (e.g., 425 1 study were randomized in parallel fashion to six (6) cohorts: or 710 microns) into the stainless steel blending container five (5) cohorts of ER ONA tablets (10 mg BID, 20 mg BID, (from Step 2). The previously screened mixture from Step 3 is 30 mg BID, 40 mg BID. 50 mg BID) and one (1) cohort using added to the container. the IR tablet formulation (100 mg QD). The trial was con 0052 Step 5: The mixture is blended to achieve a homog ducted in five (5) centers in France (registered on Clinical enous mix. Trials.gov as NCT02052128). 0053 Step 6: Approximately half of the microcrystalline 0064. The study was approved by the Ile de France III cellulose, half of the lactose monohydrate and half of the Comite pour la Protection des Personnes (a French national hydroxypropyl methylcellulose are separately screened into a ethics committee), the ANSM (French regulatory authority) larger stainless steel blending container through a screen of and individual site scientific review boards, and written appropriate mesh size (e.g., 425 or 710 microns). The blend informed consent was obtained from each study patient. from Step 5 is added to this container, and the remaining 0065 Highly purified ONA tablets can be by standard microcrystalline cellulose, lactose monohydrate and hydrox pharmaceutical chemistry purification methods by those ypropyl methylcellulose are screened into the container skilled in the art. ER formulation with release kinetics from through a screen of appropriate mesh size (e.g., 425 or 710 10-12 hours depending on tablet dose. The original study microns). design included a 20-patient expansion component. An 0054 Step 7: The mixture is blended further to achieve a 8-week dose-limiting toxicity (DLT) observation period was homogeneous mix. utilized to characterize thoroughly the safety profile, as pre vious ONA studies demonstrated a spike in the LFTs at 0055 Step 8: The mixture from Step 7 is co-screened with approximately 6 weeks of treatment. magnesium Stearate through a screen of appropriate mesh 0.066 Patients were treated until documented progressive size (e.g., 425 or 710 microns) into the container from Step 4. disease (PD) or intolerance to medication. We consider the design of this study to be in agreement with the recently Example 3 proposed guidance for phase 1 protocols for dose escalation Patients and Methods Iasonos 2015. 0056 Eligibility Example 5 0057 Inclusion Criteria Included: 0058 (1) post-menopausal female patients a 18 years of Pharmacokinetics Methods age that have been previously treated recurrent or metastatic 0067 Blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 12 progesterone receptor-expressing cancer (e.g., endometrial, (before next BID dose), and 24 (before next dose for 100 ovarian, breast cancer or uterine sarcoma) with evaluable mg IR only) hours post-ONA, as well as hour 0 on days 8, 29 disease per Response Evaluation Criteria In Solid Tumors, and 57 (just before drug intake). Plasma concentrations of version 1.1 (RECIST 1.1); ONA, mono-demethylated onapristone (M1) and other 0059 (2) patients having available tissue blocks or biopsy metabolites in plasma and urine were analyzed with a vali specimens to determine progesterone receptor (PR) and acti dated ultra-performance liquid chromatography with tandem vated progesterone receptor (APR) status; and mass spectrometry detection (UPLC-MS/MS) assay. Phar 0060 (3) patients having Eastern Cooperative Oncology macokinetic modeling was performed using Monolix Soft Group (ECOG) performance status 0-1, and signed informed ware in order to estimate PK parameters Cmax, Tmax, COnSent. AUCO-last, AUCO-8, t/2, Vd, CL, and Vc. US 2016/0166583 A1 Jun. 16, 2016
0068 Although the above description refers to particular Rich Tumors Have Poorer Disease-Free Survival Rates. aspects, it is to be understood that these aspects are merely Clin Cancer Res 2004 10: 2751 illustrative. It will be apparent to those skilled in the art that I0083. 15. Hutt E. BosqJ, Powell MA, Leblanc E, Fujiwara various modifications and variations can be made to the poly K. Herzog T.J. Coleman R L. Graham D. Clarke C, Gilles morphic forms and methods described herein. Thus, it is E. M. Zukiwski AA, Monk B.J. Clinical and pathological intended that the present description include modifications correlation of the activated form of the progesterone recep and variations that are within the scope of the appended tor (APR) in Endometrial Cancer (EC). ECC 2013, #1.002 claims and their equivalents. 0084 16. Iasonos A, Gonen M. Bosl G. J. Scientific Review of Phase I Protocols With Novel Dose-Escalation REFERENCES Designs: How Much Information Is Needed? Journal of 0069. 1. 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0099 31. Rezai K, Cottu PH, Huguet Set al. Population achieved at about 8 days following the administration of the pharmacokinetic (PPK) modeling of onapristone in extended release pharmaceutical composition to a patient patients (pts) with progesterone receptor (PR)-expressing twice per day. cancers. AACR Annual Meeting 2015. Abstract 4523. 9. A method of administering onapristone to a patient hav 0100 32. Robertson JF R, Willsher PC, Winterbottom L ing cancer comprising administering an extended release et al. Onapristone, a Progesterone Receptor Antagonist, as onapristone pharmaceutical composition twice per day to the First-line Therapy in Primary Breast Cancer. EurJ Cancer patient, wherein the extended release onapristone pharma 1999; 35: 214-218. ceutical composition comprises of at least about 2 mg to about 0101 33. Sieh W. Köbel M, Longacre TA, et al. Hormone 50 mg of onapristone. receptor expression and ovarian cancer Survival: an Ova rian Tumor Tissue Analysis consortium study. Lancet 10. The method of claim 9, wherein the extended release Oncol 2013: http://dx.doi.org/10.1016/S1470-2045(13) onapristone pharmaceutical composition is administered 70253-5. once per day. 0102. 34. Taplin M. E. Manola J, Oh Wet al. A phase II 11. The method of claim 9, wherein the onapristone it at study of mifepristone (RU-486) in castration-resistant least about 98% pure. prostate cancer, with a correlative assessment of androgen 12. The method of claim 9, wherein the amount of onapris related hormones. J Compil BJU Int 2008: 101: 1084 tone in the extended release onapristone pharmaceutical com 1089. position is selected from the group consisting of about 2 mg, (0103 35. Thigpen J. T. Brady M, Alvarez R et al. Oral Medroxyprogesterone Acetate in the Treatment of 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 37.5 mg and 50 mg. Advanced or Recurrent Endometrial Carcinoma: A Dose 13. The method of claim 9, wherein the cancer expresses Response Study by the Gynecologic Oncology Group. J the progesterone receptor. Clin Oncol 1999; 17: 1736-1744. 14. The method of claim 13, wherein the cancer is selected 0104 36. Yin P. Lin Z. Reierstad S, et al. Transcription from the group consisting of breast, prostate, ovarian, and Factor KLF11 Integrates Progesterone Receptor Signaling uterine endometrioid cancers. and Proliferation in Uterine Leiomyoma Cells. Cancer Res 2010; 70(4): 1722-30. 15. A method of treating a human Subject having a disorder What is claimed is: capable of treatment with onapristone comprising adminis 1. An extended release pharmaceutical composition com tering the extended release onapristone pharmaceutical com prising onapristone wherein onapristone is present in an position of claim 1 to the human subject twice per day, amount from about 2 mg to about 50 mg. wherein the AUC of onapristone following the administration 2. The extended release pharmaceutical composition of of 10 mg of the extended release formulation to a patient claim 1, wherein the dosage form of the pharmaceutical com twice per day is at least about 1578 ngh/ml over about 8-12 position is selected from the group consisting of tablets and hours. capsules. 16. The method of claim 15, wherein the extended release 3. The extended release pharmaceutical composition of onapristone pharmaceutical composition is administered to claim 1, wherein the purity of the onapristone is at least about the human Subject once per day. 98%. 17. A method of treating a human Subject having a disorder 4. The extended-release pharmaceutical composition of capable of treatment with onapristone comprising adminis claim 1, wherein the ratio of onapristone to inactive excipi tering to said Subject 10 mg of the extended release onapris ents is about 0.05 to about 5%. tone pharmaceutical composition of claim 1 twice per day, 5. The extended release pharmaceutical composition of claim 1, wherein the onapristone is present in an amount wherein the Cmax of onapristone in the human Subject is at selected from the group consisting of about 2 mg, 2.5 mg, 5 least about 240 ng/ml over about 8-12 hours. mg, 10 mg, 20 mg, 25 mg, 37.5 mg, and 50 mg. 18. The method of claim 17, wherein the extended release 6. The extended release pharmaceutical composition of onapristone pharmaceutical formulation is administered to claim 1, wherein the AUC of onapristone following the the human Subject once per day. administration of 10 mg of the extended release formulation 19. A method of treating a human subject having a disorder to a patient twice per day is at least about 1578 ngh/ml over capable of treatment with onapristone comprising adminis about 8-12 hours. tering to said Subject the extended release pharmaceutical 7. The extended release pharmaceutical composition of composition of claim 1 twice per day, wherein a steady state claim 1, wherein the Cmax of onapristone following the plasma concentration is achieved at about 8 days. administration of 10 mg of the extended release formulation to a patient twice per day is at least about 240 ng/ml over 20. The method of claim 19, wherein the extended release about 8-12 hours. onapristone pharmaceutical formulation is administered to 8. The extended release pharmaceutical composition of the human Subject once per day. claim 1, wherein a steady state plasma concentration is k k k k k