WCK1082
`Wockhardt Bio AG v. Janssen Oncology, Inc.
`IPR2016-01582
`
`1
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`

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`Published OnlineFirst November 2, 2035; DOI: 10.1158/1078-0432.CCR—15-i432
`
`Galeterone for Metastatic Castration-Resistant Prostate Cancer
`
`Translational Relevance
`
`Despite the recent advances in the understanding and
`treatment of metastatic castration~resistant prostate cancer
`(mCRPC), it remains a lethal disease. Androgen receptor
`signaling remains a primary target of therapy, as the under-
`standing of both the disease and mechanisms of resistance
`expand. Galeterone, a selective, multitargeted agent, is distinct
`from other mCRPC therapies in that it combines the mechan-
`isms of current agents—GYM? inhibition and AR antago—
`nism—with the novel mechanism of increasing AR protein
`degradation. These first assessments of gaieterone in mCRPC
`identified a well-tolerated dose that resulted in clinically
`significant reductions in prostate-specific antigen, and dem-
`onstrate the potential of this agent. In Vim) data and results of
`these studies have informed future investigation ofgaleterone,
`which will include Ali-related biomarker analyses.
`
`
`
`variants, such as AR-V7, which are produced in tumor cells as a
`result ofaberrant RNA splicing ofthe wildvtype AR transcript. The
`resultant truncated AR protein lacks the C—terminal domain to
`which androgen binds and is the primary site of action of
`nonsteroidal antiandrogens such as enzalutamide. Furthermore,
`splice variants have been shown to be constitutively active tran-
`scription factors, leading to the activation ofandrogen-responsive
`genes even at castrate levels of androgens [15. 1G}. Mutations in
`the AR may also contribute to resistance in CRPC, and AR point
`mutations allow activation of the receptor by nonphysiologic
`ligands (e.g., cortisol, progesterone, flutamide, bicalutamide;
`refs 17,
`18, 19). As a resuit, androgenrindependent, but
`Ail-dependent, tumor growth occurs, and tumors become resis-
`tant to therapeutic agents that alter androgen production (e.g.,
`abiraterone} or antagonize binding to the AR [e.g., bicalutamide,
`enzalutarnide). Recent data demonstrated that patients with
`detectable circulating tumor cells harboring Alt—V? had inferior
`responses to abiraterone or enzalutamide,
`including inferior
`prostatespecific antigen (PSA) response, clinical and radiograph-
`ic progression-free survival (PPS), and poor OS (12, 13).
`Galeterone is a selective, multitargeted agent that disrupts
`androgen signaling at multiple points in the pathway. Preclinical
`data have shown that galeterone is a selective potent CYP17
`inhibitor and a potent AR antagonist, but unlike other available
`agents that target androgen signaling galeterone reduces AR
`expression in prostate cancer cells by causing an increase in AR
`protein degradation (20—26). Preclinical in trim;- and in vii/'0 data
`have shown that galeterone treatment in prostate cancer models
`resulted in a significant reduction in both full-length AR and AR-
`V? splice variant levels. In addition, galeterone has been shown to
`have activity against AR point mutations T87BA [20-25] and, in
`preliminary findings, to have activity in cells expressing the AR
`point mutation F876L (27).
`This article reports the safety and efficacy of galeterone in a
`phase 1 study, Androgen Receptor Modulation Optimized for
`Response (ARMORI), and the dose-escalation component of the
`phase 11 ARMOR2 study (ARMOR2 part 1). The dosewescalation
`component ofARMORZ was conducted to determine the phase II
`and phase III dose of a galeterone spray dry dispersion [SDD}
`tablet. This formulation was developed after a healthy volunteer
`
`study confirmed a significant food effect with the capsule formu-
`lation that was used in ARMORI (Supplementary Data), The SDD
`tablet formulation was shown in a healthy volunteer study to not
`be affected by food, providing similar exposure [area under the
`concentration-time curve, AUC) in fed and fasted states (28).
`Results of this study also demonstrated equivalent serum con—
`centrations using either 1,700 mg ofthe SDD tablet or2,600 mg of
`the capsule, which was the highest dose studied in ARMORI.
`Thus, the dose-escalation portion of ARMOR2 was conducted to
`evaluate the safety and tolerability of escalating doses ofthe SDD
`formulation and to determine the recommended dose for
`ARMORZ part 2 and ARMORB.
`
`Patients and Methods
`Patients
`
`Eligible men had histologically confirmed nonmetastatic [M0]
`or metastatic [M1] adenocarcinoma of the prostate, a life expec-
`tancy of >12 weeks, and progressive disease despite ongoing
`androgen-deprivation therapy. Patients were required to have
`progressive disease according to Prostate Cancer Clinical Trials
`Working Group 1 ]PCWGI] criteria (29) in ARMORI, or PCWCZ
`criteria (30) in ARMOR2 part 1, ongoing treatment with gonad-
`otropin-releasing hormone analogs or orchiectomy (serum tes-
`tosterone <50 mg/dL), and an Eastern Cooperative Oncology
`Group (ECOC) performance status of S1. ARMORI excluded
`patients who had previously received chemotherapy, ketocona-
`zole, abiraterone, or enzalutamide. ARMOR2 part 1 permitted the
`enrollment of abirateronerrefractory patients, provided it had
`been discontinued 24 weeks before enrollment and that the
`duration of therapy was 26 months before PSA progression or
`>6 weeks with documentation of an initial response followed by
`PSA progression. Previous ketoconazole treatment was permitted
`upon agreement between the investigator and the study sponsor.
`Patients with nonhepatic visceral metastases and/or tumor-asso~
`ciated bone pain that required active pain management were
`excluded from ARMORI. Patients with indeterminate lung
`nodules were eligible. Other exclusion criteria included any
`previous radium-223, strontium, or samarium therapy within 8
`weeks ofenrollment; radiotherapy 34 weeks before enrollment or
`completed radiotherapy in ARMOR]; or radiotherapy S3 weeks
`(:2 weeks for single-fraction radiotherapy) in ARMORZ pan 1.
`Patients were excluded if they had previous treatment with inves-
`tigational drugs or agents that could have interfered with the
`efficacy and safety assessments. Patients with abnormal labora-
`tory test results, including serum creatinine level >1.5 times the
`upper limit of normal [ULN), liver function test results >1.5 x
`ULN, hemoglobin level 59.0 gde, platelet count 3100 x 109,11,
`absolute neutrophil count 51.5 x 109/1, and serum potassium
`level <35 mmolfL, were ineligible, as were those with serious
`concurrent illnesses or conditions, including heart failure, uncon-
`trolled hypertension, angina, active autoimmune disease, or
`gastrointestinal disorders or gastric bypass surgery that could have
`interfered with study medication absorption. Written informed
`consent was obtained from participants before enrollment.
`
`Study design
`ARMORi (NCT00959959) was a phase I, multicenter, open-
`label, dose-escalation study conducted in collaboration with the
`Department of Defense Prostate Cancer Clinical Trials Consor-
`tium, designed to assess the tolerability, safety, and effi cacy oforal
`
`www.aacrjournals.org
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`Clln Cancer Res: 22(6) March 15, 2016
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`Published OnlineFirsi November 2, 2015; DOI: 10.1158/1078~D432.CCR-15-1432
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`Montgomery et al.
`
`galeterone for chemotherapy-naive patients with CRPC. The
`primary goals were to find the optimal dose of galeterone with
`an acceptable safety profile, defined as an observed dose-lim-
`iting toxicity (DLT) rate of 535%, and to identify a dose for
`further phase II study. The dose equivalence component of
`ARMOR2 (i.e,, part I; NCT01709734) evaluated the pharma-
`cokinetics (PK), safety, and efficacy of a new formulation of
`galeterone with improved bioavailability. A micronized pow—
`der formulation (capsule) was used in ARMORI and an SDD
`formulation was used in ARMORZ part 1. These studies were
`designed and monitored in accordance with Sponsor proce-
`dures, which comply with the ethical principles of Good
`Clinical Practice, as required by the major regulatory author“
`ities, and in accordance with the Declaration of Ilelsinki and
`the FDA regulations. The protocols were approved by the
`institutional review board of each study site.
`In ARMORI, galeterone capsules (micronized powder, 325
`mg) were administered orally as (i) 650 mg in the evening, (ii)
`975 mgin the evening, (iii) 975 mg in the morning, (iv) 1,300 mg
`in the evening, (v) 1.950 mg in the evening, (vi) 1,950 mg divided
`into morning and evening doses, (vii) 2,600 mg in the evening, or
`(viii) 2,600 mg divided into morning and evening doses, accord-
`ing to the cohort they entered. All doses were administered with a
`patientaselected meal, except for the 975 mg morning dose cohort,
`which received a high-fat, highecalorie nutritional supplement
`(Novasource Renal, Nestle llealthCare Nutrition, Florham Park,
`NJ) in place ofthe meal. Enrollment target was 6 patients per dose
`cohort. If an acceptable safety profile was determined by the
`internal monitoring committee (lMC; DLT rate 535% or 52 of
`5 patients in cohorts of 6 patients), subsequent dose levels and
`schedules were opened for enrollment. If 23 of 6 patients expe
`rienced DLTs, dose de-escalation was required. DLTs were defined
`as any study drug—related grade 3 or higher adverse event [AEU'
`National Cancer Institute Common Terminology Criteria for
`Adverse Events (CTCAE) version 4.0] considered to be possibly,
`probably, or definitely related to the study drug.
`In ARMOR2 part 1, galeterone SDD tablets (425 mg) were
`administered at doses of 1,700, 2,550, and 3,400 mg once daily
`with the morning meal. Enrollment target was 6 patients per dose
`level. Dose escalation occurred when no clinically significant
`grade 2 or greater sustained AEs or serious, unexpected grade 3
`or higher AEs occurred in a dose group 2 weeks after the last
`patient in that cohort received his first dose.
`The planned treatment duration ofboth studies was 12 weeks,
`with optional extension closing for eligible patients based on
`safety and tolerability during the lzeweek phase. Extension dos-
`ing was continued until the patient withdrew, experienced unac—
`ceptable toxicity, the disease progressed, or the patient died.
`
`Assessments
`Safety assessments, conducted at baseline and every 2 weeks
`during the 12-week study and every 4 weeks during the optional
`extension phase, included physical examination, vital signs, elec-
`trocardiogram (ECG), serum chemistry, hematology, urinalysis,
`and performance status. AEs that occurred during the study and up
`to 30 days after the last dose of study drug were collected, coded
`according to Medical Dictionary of Regulatory Activities, version
`12.1, and graded using CTCAE version 4 .0, PSA was determined at
`each study visit.
`In the first 4 closing cohorts ofARMORI, blood samples for PK
`analysis were obtained predose and at 4 hours on day 1. In the
`
`remaining cohorts, blood samples were obtained before (hour
`0) and 1, 2, 4, and 6 hours after the first dose on day 1. At all
`remaining visits,
`if the regimen for the cohort
`included a
`morning dose, blood samples were obtained at 6 hours after
`their dose, for all other cohorts, blood samples were obtained
`at any time during the visit. In ARMORZ part 1, blood samples
`for PK analyses were obtained before (hour 0) and 2, 3, 4, 5,
`and 6 hours after the day 1 dose, and predose on days 7, 14, 21,
`28, and 84, Additional samples were obtained in consenting
`patients on day 1 at S, 12, 16, and 24 hours postdose and on
`day 84 at 2, 3, 4, 5, 6, 8, 12, 16, and/or 24 hours postdose.
`Blood samples were also obtained at each study visit of
`ARMOR2 part 1 for determination ofpregnenolone, 17-hydro-
`xyprogesterone, deoxycorticosterone, 11-deoxycortisol, cortico-
`sterone, cortisol, dehydroepiandrosterone sulfate (DIIEAS),
`androstenedione, and testosterone concentrations.
`
`Data Analysis
`Efficacy endpoints included the proportion of responders [PSA
`decrease 250% [PSASO] and 230% (1351960)), maximal decrease
`in PSA from baseline to 12 weeks or PSA nadir, changes from
`baseline in tumor response as assessed by bone scan and CT or
`MR1 using PCWCZ and RBCIST v1.1. PSA efficacy was based on
`the intentvto-treat population (UT), defined as enrolled patients
`who received at least 1 dose ofstudy drug. Response was based on
`measurable disease in both studies. Time to progression, PFS
`defined as the time from first dose of study drug until objective
`CRPC progression or death, whichever occurred first, and 08 were
`the endpoints assessed in the ARMORI extension phase, Descrip-
`tive statistics were used for most variables (it, mean, SD, median,
`minimum, and maximum forcontinuous variables and frequency
`and percentage for categorical variables).
`
`Results
`Patients
`Baseline patient and disease characteristics are presented
`in Table 1, In ARMORl, 49 patients were enrolled in 8 cohorts,
`with 6 patients in each, except cohort 4, which enrolled 7 patients.
`Twelve patients discontinued the study before completion of 12
`weeks because of treatment-emergent AEs [TEAEs; n = 5; nausea,
`chronic obstructive pulmonary disease exacerbation (event onset
`before (losing), elevated aspartate aminotransferasefalanine ami-
`notransferase levels
`(AST/ALT; n = 2), acute renal
`failure
`[reversible after resolution of rhabdomyolysis, which occurred
`while the patient was receiving simvastatin therapy and became
`evident after the patient fell], disease progression (n = 5), or
`withdrawal of consent/personal choice [it = 2; Table 2)], Twenty-
`two of the 37 patients who completed the study were eligible for
`the optional extension phase, and 21 patients were dosed. Over-
`all, all patients received 650 to 2,600 mg galeterone daily for<1 to
`20 months. In ARMOR2 part 1, 28 patients were enrolled in 3
`dosing cohorts, with 6 patients in the 1,700-mg cohort, 14 in the
`2,550-mg cohort (abiraterone-resistant, n = 3), and S in the
`3,400-mg cohort. Six patients discontinued the study before 12
`weeks because of TEAEs [n = 4; angioedema (in an African-
`American who was receiving the angiotensinuconverting enzyme
`inhibitor, lisinopril), rash, weakness, and tremulousness] or dis-
`ease progression (n : 2). All 3 patients with abiraterone-resistant
`disease completed the 12-week phase ofthe study. Nineteen of22
`patients who completed the study participated in the optional
`
`1358 Clln Cancer Res; 22(6) March 15, 2016
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`Published OnlineFirst November 2, 2015; DOI: 10.1158/1078-0432.CCR-15-1432
`
`Tablet. Baseline characteristics
`
`ARMOR1
`(N = 49)
`68 (47a89)
`
`ARMORZ Part1
`(N = 28)
`70 (48-90)
`
`43 (are)
`3 (6.1)
`1 (2.0)
`2 (4‘1)
`25 (51.0)
`25
`15
`9
`7
`6
`3
`17
`
`49 (100)
`l (2)
`27 (55)
`24 (49)
`NA
`NA
`
`24 (85.7)
`2 (7.1)
`1 (3.6)
`1 (3.6)
`24 (85.7)
`24
`10
`8
`1
`1
`0
`11
`
`28 (100)
`2 (7.1)
`16 (57.1)
`12012.9)
`3 (i0.7)
`0
`
`characteristic
`Age. median (range). y
`Ethnicity, n (%)
`White
`African-American or black
`Asian
`Other
`Metastatic disease (M1). in 0%.)
`Bone. n
`Nodal. n
`Bone and nodal. n
`Visceral (liver and/or lung). n
`Visceral and bone. 17
`Visceral and nodal. n
`Soft tissue (not nodal. liver. or lung). 17
`Previous therapies. n (5%)
`Medical and/or surgical castration
`Immunotherapy
`Radiotherapy
`Surgery
`Abiraterone
`Enzalutamide
`ECOG, n (‘36)
`O
`1
`Missing
`Gleason score. median (range)6
`PSA. median (range). ng/dL
`Abbreviations: NA. not applicable.
`6Data were missing in 2 patients in ARMOR] and l patient in ARMOR 2 Part 1.
`
`45 (91.8)
`4 (8.2)
`0
`7 (6-10)
`24 (6-2005)
`
`22 (78.6)
`5 (17.9)
`l (3.6)
`3 (5—10)
`17.5 (SJ-6.760)
`
`extension phase; 2 of the patients with abiraterone-resistant
`disease were not eligible for the extension because of disease
`progression (Table 2). Overall duration oftherapy ranged from <1
`month to 14 months.
`
`Safety and tolerability
`ARMORI. Safety reviews were completed after all patients were
`closed in each cohort and the mac recommended continued
`escalation following review of all doses. There were 2 deaths, 1
`from disease progression and 1 from acute septic shock followed
`by acute metabolic acidosis and renal failure, which was not
`related to galeterone. All patients experienced at least 1 TEAE
`during the 12-week phase, with most being mild or moderate in
`severity (91.5%) and comparable among cohorts. The majority
`(73%) of the A125
`required no action. The most common
`TEAEs were fatigue [17 patients (34.7%)], increased AST level
`
`Gaieterone for Metastatic Castration-Resistant Prostate Cancer
`
`[16 patients (32.7%)], increased ALT level [15 patients (30.6%)],
`nausea [12 patients (24.5%)], diarrhea [11 patients (22.4%)], and
`pruritus [11 patients (22.4%); Table 3]. The most common
`treatmenterelated TEAEs were increased AST level
`[7 patients
`(14.3%)], nausea [5 patients (10.2%)], increased bilirubin level
`[4 patients (8.2%)], fatigue [4 patients (8.2%)], and diarrhea
`[3 patients (6.1%)]. The majority of patients (85.7%) in the
`extension phase experienced mild or moderate TEAEs that were
`consistent with those reported during the treatment phase.
`
`ARMORZ Part 1. Galeterone tablets were well tolerated at all
`doses, as assesSed by the IMC. Safety reviews were completed after
`all patients were closed in each cohort. and the mac recommended
`continued escalation. Most patients [93%) experienced at least 1
`TEAE, with the majority (91%) being grade 1 or 2 in severity and
`comparable among cohorts. Most (72%) AEs required no inter-
`vention. There were no DLTs at any dose level. The most common
`TEAEs were nausea [13 patients (46.4%)], fatigue [9 patients
`(32.1%)], pruritus [9 patients (32.1%)], vomiting [8 patients
`(28.6%)], and decreased appetite [6 patients (21.4%).- Table 3].
`The most common treatment-related TEAEs were nausea
`[10 patients (35.7%)]; pruritus [9 patients (32.1%)]; fatigue,
`vomiting, and decreased appetite [6 patients (21.4%] for each);
`and constipation, diarrhea, increased ALT level, and dizziness
`[3 patients (10.7%)] for each). Although edema and hypokalemia
`were observed, they were independent events in different patients
`and no combined apparent mineralocorticoid excess events were
`seen (Table 4).
`
`Pharmacokinetics
`The PK analysis plan of ARMORI was not designed to fully
`characterize the PK of galeterone. There was no consistency or
`dose dependence with respect to plasma concentrations and
`regimen. There was little or no difference in mean concentrations
`in the single daily doses. with only the ESQ—mg dose demonstrat-
`ing lower mean concentrations. and the PK of the 975-mg dose
`was no different after the supplement. compared with a patient-
`selected meal. Dividing the dose did not have a significant effect
`on exposure (AUC).
`The PK analysis plan of ARMOR2 was not designed to fully
`characterize the PK of galeterone. The ARMORZ part
`1 PK
`parameters after single doses of 1.700. 2,550, and 3,400 mg
`of the SDD tablet formulation were similar among doses.
`Exposure, expressed as AUC from predose to 6 hours postdose
`(AUC0_6), was 2,646 -_i: 1.748 h - ngme. 2,684 :l: 2,043 h- ng/‘mL,
`
`Table 2. Treatment cohorts and patient disposition
`ARMORl—Galelerone capsules
`SN: 49)
`
`—
`Entered
`extension
`phase, 11
`3
`2
`3
`
`ARMORZ Part l—Galeterone 500 tablets
`(N = 281
`Completed
`12-week
`study, 11
`6
`11
`5
`
`Enrolled,
`n
`6
`14
`8
`
`Entered
`Extension
`phase, :1
`6
`9
`4
`
`Cohort
`1.700 mg
`2.550 mg
`3,400 mg
`
`Completed
`12-week
`Enrolled,
`study, it
`n
`Dosing cohort
`3
`6
`650 mg with meal
`5
`5
`975 mg with meal
`5
`6
`1.300 mg with meal
`5
`7
`1.950 mg with meal
`4
`6
`975 mg with supplementa
`5
`6
`1.950 mg divided doses with meal
`5
`6
`2,600 mg with meal
`5
`6
`2,500 mg divided doses with meal
`Novasource Renal. Nestle HealthCare Nutrition. Florham Park. New Jersey,
`bThree patients were eligible for the extension phase; however. only 2 patients were closed with gaieterone.
`
`24 2
`
`b
`
`23 “
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`www.aacrjournals.org
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`Published OnlineFirst November 2, 2015; DOI: 10.1158l1078—0432.CCR-154432
`
`Montgomery et al.
`
`Table 3. Treatment-emergent AEs occurring in >10% of patients in ARMOR] or ARMORZ Part1
`ARMORl
`(N = 49)
`
`Grade 1 or
`2, n (9%)
`A5
`5 (10.2)
`Abdominal pain
`7 (14.3)
`increased alkaline phosphatase level
`7 (14.3)
`increased ALT level
`6 (12.2)
`Decreased appetite
`6 (12.2)
`Arthralgia
`13 (26.5)
`increased AST level
`i (2.0)
`Back pain
`6 (12.2)
`increased bllirubin level
`5 (10.2)
`Constipation
`7 (14.3)
`Cough
`11 (22,4)
`Diarrhea
`3 (6.1)
`Dizziness
`0
`Fall
`16 (32.7)
`Fatigue
`12 (24.5)
`Nausea
`11 (22.4)
`Pruritus
`5 (10.2)
`Rash
`4 (8.2)
`Urinary tract infection
`6 02.2)
`Vomiting
`5 (10.2)
`Decreased weight
`Abbreviations: ALT, alanine aminotransterase; AST, aspartate aminotransterase.
`
`Grade 3 or
`higher, a ($6)
`0
`0
`8 (16.3)
`0
`0
`3 (6.1)
`0
`1 (2.0)
`O
`0
`0
`0
`0
`1 (2.0)
`0
`O
`0
`0
`O
`0
`
`ARMORZ Part 1
`(N : 28)
`
`Grade 3 or
`higher, n (as)
`0
`0
`3 (10.7)
`0
`0
`1 (3.6)
`0
`0
`1 (3.6)
`0
`1 (3.6)
`0
`0
`0
`0
`0
`1 (3.6)
`0
`0
`0
`
`Gradei or
`2,1106)
`1 (3.6)
`0
`1 (3.6)
`6 (21.4)
`1 (3.6)
`1 (3.6)
`3 (10,7)
`O
`3 (10.7)
`3 (10.?)
`4 (14.3)
`3 (10.7)
`3 (10.7)
`9 (32.1)
`13 (46.4)
`9 (32.1)
`0
`4 (14,3)
`B (28.6)
`4 (14.3)
`
`and 2,528 :i: 1,529 b - ng/mL for the 1,700, 2,550, and 3,400 mg
`doses, respectively.
`
`Efficacy endpoints
`ARMORI. The TIT population for PSA efficacy included 49
`patients. Across all doses tested, 24 of 49 (49.0%} achieved a
`PSASO and 11 of 49 patients (22.4%) demonstrated PSA50
`(Fig, 1A). During the study, one patient in the 650 mg/d group
`discontinued his gonadotropin-releasing hormone analog and
`one patient in the 975 mg/d group underwent transurethral
`resection of the prostate. Excluding these patients, across groups
`the PSASO was 51.1% (24/47) and the PSA50 was 23.4%(11/47).
`An increase in response rate was observed with higher doses. At
`the 2,600 mg dose, 9 of 12 patients (75.0%) demonstrated a
`PSA3O and 5 of12 patients (41.7%) demonstrated a PSA50.There
`was no difference in PSA response between groups that had
`divided dosing and groups that had once-daily dosing. Of the
`evaluable patients [those with measurable target lesions at screen
`ing or baseline who had a follow-up scan at the 14-week (final)
`study visit; 71 :- 17], 2 patients had a partial response (PR) and 10
`patients had stable disease (SD), according to RECIST. In the
`extension phase, disease progression ultimately occurred in 20 of
`the 21 patients. No consistent trends were observed in time to
`progression (range, 14—592 days), PFS, or OS [shortest 189 days,
`cohort 3 (1.300 mg/d)| between treatment cohorts. Best overall
`response assessed by RECIST was SD in 13 of17 patients (76.5%)
`in the extension phase;
`the remaining 4 patients had disease
`progression.
`
`Table 4. Summary of Potential AME AEs in ARMOR1 or ARMORZ Part 1
`Number of
`Attribution:
`AE
`incidences
`related/unrelateda
`Grade 2 hypokalemia
`1
`1/0
`Grade 3 hypokalemia
`3
`1/2
`Grade 1 peripheral edema
`1
`0/1
`Grade 2 peripheral edema
`3
`2/1
`aAll events were individual occurrences and not considered AME symptoms.
`
`ARMOR2 Part 1. The HT population for PSA efficacy in treatment?
`na'ive patients included 25 patients. Three patients had received
`prior abiraterone treatment. Across the 3 doses in treatment-naive
`patients, the decline in PSA from baseline in the ITT population
`was 230% in 16 of 25 patients (64.0%) and 250% in 12 of 25
`patients (48.0%). In the 2,550-mg dose cohort, 8 of 11 treatment—
`naive patients (72.7%) had a 230% decline in PSA from baseline
`and 6 of 11 patients (54.5%) had a 250% decline in PSA from
`baseline.
`in the 1,700—mg dose cohort 50% (3/6 patients)
`achieved a PSASO and PSA50.
`in the 3,400 mg dose cohort,
`62.5% (5/8 patients) achieved a PSA30 and 37.5% (3/8 patients)
`achieved a PSASU (Fig. 13). One patient in the 2,550-mg/d group
`had only 1 post-baseline PSA measurement
`(performed at
`2 weeks) and 1 patient in the 3,400 mg/d group had no post
`baseline measurement of PSA. Excluding these patients,
`the
`PSA30 and PSASO were 80% and 60% in the 2,550 rug/cl group,
`and 71.4% and 42.9% in the 3,400 mg/d group. Ofthe 3 patients
`treated with 2,550 rng/d who had prior treatment with abirater-
`one, 1 patient (33%) achieved PSA30. 1 patient had a maximal
`percent change of —2%, and 1 patient had an increase from
`baseline. Of the 26 evaluable patients with measurable disease
`atbaseline, 20 (76.9%) patients had SD and 1 patient had PR at 12
`weeks.
`
`Steroidogenic pathway markers
`Galeterone resulted in overall reductions in median serum
`testosterone, Dl-IEAS, and androstenedione concentrations.
`Median corticosterone level was increased from a median baseline
`of 204 ng/dL to 1,377.5 ng/di. at week 12, and cortisol and
`deoxycorticosterone levels were generally unchanged (Table 5).
`
`Discussion
`
`Results of ARMORI and ARMOR2 part 1 demonstrated that
`galeterone, an agent that previous studies have shown inhibits
`androgen production, blocks the ligand-binding domain of AR,
`and suppresses AR levels in virro, is safe and shows promising PSA
`
`1360 Clin Cancer Res; 22(6) March 15, 2016
`
`Clinical Cancer Research
`
`Downloaded from clincancerreseacdournalsorg on March 3?, 2017. © 2016 American Association for Cancer Research.
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`5
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`

`Published OnlineFirst November 2, 2015; DOI: 10.1158/1OTB-0432.0CR-15-1432
`
`Galeterone for Metastatic Castration-Resistant Prostate Cancer
`
`975 mm
`In=12l
`
`1.300 mgld
`tn=6i
`
`1,950 mgr‘d
`in=133
`
`2.600 mm
`(n=12)
`
`l
`550 mgrd a
`01:6)
`I
`f
`s
`’
`3
`a
`i
`5
`I
`
`"mm"- m-“m-"n
`----------" -‘----------------------
`
`--------‘-----
`-----------
`——-------“-- -------""""-“‘-----
`
`------
`---------""-"
`
`"-
`
`100
`
`0
`
`75
`
`r:
`a
`‘r
`E
`s 5°
`s
`E 25
`o
`c
`a:
`g’
`g
`0 25
`q _
`m
`o.
`'5 —50
`x
`ll
`E '75
`
`-
`Figure 1.
`A, the maximal percentage of change
`in PSA from baseline at 12 weeks by
`.
`.
`.
`total daily dose In treatment-naive
`patients in ARMOR1(n : 49).
`Patterned data points reflect 1 patient
`.
`who discontinued his gonadotropinw
`releasrng hormone analog (650 mg/d
`group) and 1 patient who underwent
`transurethral resection of the prostate
`(975-mg/d group). B. the maximal
`percentage of change in PEA from
`baseline by total daily dose in
`evaluable treatment-naive patients in
`
`ARMOR2 Part 1 (n z 25} Patterned
`data point reflects a patient who only
`had i post-baseline PSA measurement
`(at 2 weeks). One patient in the
`3.400 mg/d group (n = 8) is not
`included in the graph because no post-
`baseline PSA measurements were
`completed. Abiraterone-refractory
`patients (N = 3) were not inciuded in
`this analysis. Reference lines: green,
`—50%,‘ orange, —30%. '. maximal PSA
`values >100% increase from baseline.
`
`400
`
`100
`'HI"I
`
`InD
`
`M"I
`
`1,700 my”
`m = 5)
`
`2550 my“
`m :1”
`
`“on maid
`(n = 7}
`
`,
`
`mm
`
`I
`
`NUI
`
`is.Do
`
`I
`
`'HlL'I'I
`
`I
`
`.4 OD
`
`
`
`MaximalPSAchangefrombaseline(“15.)
`
`
`
`
`
`responses in patients with rnCRPC. Results from phase 1 healthy
`volunteer PK studies and the PK results ofARMORZ part 1 support
`a 2,550 rug/d dOse of galeterone SDD tablet for use in future trials.
`All doses tested had similar safety and tolerability profiles.
`Results of these studies demonstrate that galeterone is well tol-
`erated in men with CRPC, with infrequent grade 3 and 4 toxicities.
`The most common treatment—related AEs were nausea, vomiting,
`
`Table 5. Median (range) concentrations of the steroidogenic pathway markers
`in ARMORZ Part i
`
`Steroid
`Testosterone. ng/dL
`Androstenedione, ng/dL
`DHEAS, ug/dL
`Corticosterone, ng/dL
`Deoxycorticosterone. ng/dL
`Cortisol. pig/6L
`
`Baseline
`7.5 (3—22)
`32 (7-81)
`37.5(<15-220)
`204 (do-874)
`<16 (<lG—18)
`14,7 (LB-28.7)
`
`Median (range)
`Week 12
`2 (<i-14)
`14 (<S~34)
`18 (<15—i05)
`1.3775 (ST-4,375)
`<16 (<i6~89)
`18.i (4.i-35)
`
`fatigue, pruritus, and decreased appetite. Of these events. the vast
`majority [~90%] were grade 1 or 2 and did not require any
`intervention. Of note, there were no apparent mineralocorticoid
`excess AEs, supporting results of preclinical studies demonstrating
`the specificity of galeterone for CYP17 lyase compared with
`hydroxylase (19]. This hypothesis is further supported by the
`steroidogenic marker results showing no change in deoxycorti-
`costerone or cortisol and a small
`increase in corticosterone,
`relative to a large increase observed with abiraterone even in the
`absence ofcoadministration of steroids with galeterone (31). The
`reductions in testosterone are slightly less than those seen at full
`dose abiraterone, but similar to that found in the dose escalation
`study [31).
`Significant PSA declines were observed with all dose levels,
`Patients in ARMORI had an overall PSASO and PSASO of49% and
`22%, respectively, with the highest close (2,600 mg) showing
`PSASO and PSASO of75% and 42%, respectively. In ARMORZ part
`1, 2,550 mg of the SDD tablet formulation, the dose found to
`
`wwwaacriournalsorg
`
`Clin Cancer Res; 22(6) March 15. 2016
`
`3361
`
`Downloaded from clincancerres.aacrjournalsorg on March 3615, 2017. © 2016 American Association for Cancer Research.
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`6
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`Published OnlineFirst November 2, 2015; DOI: 10.1158l1078-0432.CCR-15-1432
`
`Montgomery et al.
`
`provide exposure similar to that of 2,600 mg of the capsule,
`resulted in greater PSASO and PSASO of 80% and 60%, respec—
`tively. These results are comparable with those observed in phase 1
`and 11 trials of abiraterone and enzalutamide (8. 11, 31). Of
`note,
`these results were marginally better than the 3,400 mg
`(PSA30 = 71%, PSASO = 43%) and 1,700 mg (PSA30 = 50%,
`PSASO = 50%) doses.
`Although ARMORI showed that increasing the dose resulted in
`a better PSA response, a phase 1 healthy volunteer PK study
`showed that the capsule formulation was confounded by a food
`effect and resulted in exposure that plateaued above 1,950 mg
`(Appendix; ref. 28). The lack of a clear food effect in ARMOR]
`could be attributed to the study design, in thatthe blood sampling
`strategy was not optimal for assessment of PK parameters, and
`patienteselected meals precluded assessment of the effect of fat
`and calories.
`
`ARMORZ part 1 served as a bridging study between the original
`capsule formulation and the SDD tablet formulation, which was
`developed to have improved relative bioavailabiiity over the
`capsule. In PK studies in healthy volunteers, the SDD tablet was
`shown to result in dose-related increases in exposure that were
`similar in fed and fasted states that plateaued at doses above
`2,550 mg (32). In addition, it was found that the exposure after
`1,700 mg ofthe SDD tablet was similar to that with 2,600 mg of
`the original capsule formulation—the dose in ARMORi
`that
`resulted in the best efficacy numbers (28). ARMORz part
`1
`evaluated increasing doses of the SDD tablet formulation starting
`at the 1,700 mg dose. The PK results of this study showed that
`there was no increase in exposure with higher doses. Although the
`lack ofincrease in exposure between the 1,700 and the 2,550 mg
`dose was not consistent with earlier PK evaluations of the SDD
`tablet, it could again be attributed to study design, in that the
`sampling strategy was not optimal for a full PK assessment. The
`results from the PK, safety and PSA decline data support the choice
`ofthe 2,550 mg dose for use in phase Ii and III clinical studies.The
`phase II studies have been completed and are in follow—up, and
`the phase III study is planned (ARMOiB-SV). The ability of
`galeterone to target splice variant AR through enhanced degrada-
`tion suggests that it may have potential activity in tumors expres-
`sing these resistant variants. The phase III, ARMOR3-SV study will
`target splice variant (AR-V7) positive tumors and is based on PSA
`responses seen patients with C-terrninal loss in the treatment
`naive cohort ofARMOR2 (33).
`
`Conclusion
`
`The efficacy and safety results from ARMOR] and ARMORZ
`part 1. and the PK results from phase I healthy volunteer studies
`and ARMOR2 part 1 support the recommended dose of galeter—
`one 2,550 mg daily taken with food for ARMORZ part 2 and the
`
`phase III study (ARMORS-SV) using the SDD tablet formulation
`with improved bioavailability. Caleterone is well tolerated in
`CREE patients and demonstrates pharmacodynamic changes
`consistent with its selective multifunctional AR signaling inhibi-
`tion. The analysis of galeterone is ongoing in expanded patient
`cohorts in ARMORZ part 2 and is ongoing for a phase III trial
`(ARMOR3-SV) comparing galeterone with enzalutamide in treat-
`ment-naive patients with mCRPC whose prostate tumors express
`the AR-V7 splice variant.
`
`Disclosure of Potential Conflicts of Interest
`L.T. Nordquist is a consultant/advisory board member for Bayer Pharma-
`ceuticals. WJ. Edenfield reports receiving speakers bureau honoraria from
`Astellas and Novartis. K.]. Ferrante holds ownership interest
`(including
`patents) in, and is a consultant/advisory board member for Tokai Pharmaceu-
`ticals. M-E. Taplin reports receiving commercial research grants, other com