Phase 1/2 Trial of Orteronel (TAK-700) – an Investigational 17,20-Lyase

Author Manuscript Published OnlineFirst on January 13, 2014; DOI: 10.1158/1078-0432.CCR-13-2436 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Inhibitor – in Patients with Metastatic Castration-Resistant Prostate Cancer

Authors:

Robert Dreicer1, David MacLean2, Ajit Suri2, Walter M. Stadler3, Daniel Shevrin4, Lowell

Hart5, Gary R. MacVicar6, Omid Hamid7, John Hainsworth8, Mitchell E. Gross10, Yuanjun

Shi2, Iain J. Webb9, and David B. Agus10

Author affiliations:

1Cleveland Clinic, Cleveland, OH, USA

2Takeda Pharmaceuticals International Company, Cambridge, MA, USA

3University of Chicago, Chicago, IL, USA

4NorthShore University Health System, Evanston, IL, USA

5Florida Cancer Specialists, Fort Myers, FL, USA

6Northwestern University Feinberg School of Medicine, Chicago, IL, USA

7The Angeles Clinic & Research Institute, Los Angeles, CA, USA

8Sarah Cannon Cancer Research Institute, Nashville, TN, USA

9Millennium: The Takeda Oncology Company, Cambridge, MA

10University of Southern California Westside Cancer Center, Beverly Hills, CA, USA

Corresponding author:

Robert Dreicer, M.D., M.S., FACP, FASCO

9500 Euclid Ave R35, Cleveland, OH 44195, USA

Phone: 216-445-4623

Fax: 216-445-2360

Email: [email protected]

1 Dreicer_201 manuscript_28Oct2013

Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 13, 2014; DOI: 10.1158/1078-0432.CCR-13-2436 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Running title: Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC (limit 60

characters)

Keywords: TAK-700, orteronel, castration-resistant prostate cancer

Funding: Takeda Pharmaceuticals International Company

Statement of originality: The authors confirm that this manuscript contains original

material.

Conflicts of Interest

Employment: DBM, AS, and YS (Takeda Pharmaceuticals International Company); IW

(Millennium: The Takeda Oncology Company); Consultant or advisory role: RD, WMS, DBA

(Millennium: The Takeda Oncology Company); Honoraria: RD (Millennium: The Takeda

Oncology Company); Research support/travel grant: OH, MEG (Millennium: The Takeda

Oncology Company); No conflicts to disclose: DS, LH, GRM, JH

Journal: Clinical Cancer Research

Article type: Cancer Therapy: Clinical

Statement of translational relevance: 121 (limit 120–150 words)

Summary word count: 239 (limit 250 words)

Word count: 3071 (limit 5000 words for main body text only)

Figures/tables: 3/3 (limit 6 Figures/Tables in total)

References: 24 (limit 50)

Supplemental materials: 1 Table

2 Dreicer_201 manuscript_28Oct2013

Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Prior presentations of this study:

Agus DB, Stadler WM, Shevrin DH et al. Safety, efficacy, and pharmacodynamics of the

investigational agent TAK-700 in metastatic castration-resistant prostate cancer (mCRPC):

Updated data from a phase I/II study. ASCO Meeting Abstracts 2011;29 (15_suppl):4531.

Agus DB, Stadler WM, Shevrin D et al. Safety, efficacy, and pharmacodynamics of the

investigational agent TAK-700 in metastatic castration-resistant prostate cancer (MCRPC):

Updated data from a phase 1/2 study. Presented at the 34th Congresso Brasileiro de

Urologia, Florianópolis, Santa Catarina, Brazil, November 22-26, 2011.

Agus DB, Stadler WM, Shevrin D et al. Safety, efficacy, and pharmacodynamics of the

investigational agent orteronel (TAK-700) in metastatic castration-resistant prostate cancer

(mCRPC): Updated data from a phase 1/2 study. Presented at the 20th Malaysian Urological

Conference-Asia Pacific Society of Uro-Oncology Conference, Kuala Lumpur, Malaysia,

November 25-27, 2011.

Gross M, Shevrin D, Dreicer R et al. Phase 1/2 Study of TAK-700, an Investigational 17,20-

Lyase Inhibitor, in Chemotherapy-naïve Patients with Metastatic Castration-Resistant

Prostate Cancer (mCRPC): Safety, Efficacy, and Evaluation of Circulating Tumor Cells

(CTCs). Presented at the 3rd European Multidisciplinary Meeting on Urological Cancers

(EMUC), Barcelona, Spain, November 4-6, 2011.

Agus DB, Stadler WM, Shevrin D et al. Safety, efficacy, and pharmacodynamics of the

investigational agent orteronel (TAK-700) in metastatic castration-resistant prostate cancer

(mCRPC): Updated data from a phase 1/2 study. ASCO-GU Meeting Abstracts 2012; J Clin

Oncol 2012;30 (suppl 5):(Abstr 98).

3 Dreicer_201 manuscript_28Oct2013

Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

MacLean DB, Stadler WM, Shevrin D et al. Selective inhibition of androgen synthesis by

orteronel (TAK-700), an investigational 17,20-lyase inhibitor, in men with metastatic castrate

resistant prostate cancer (mCRPC). Poster presented at the Endocrine Society’s 94th

Annual Meeting & Expo, June 23–26, 2012, Houston, Texas, USA.

Role of the funding source

Employees of Takeda Pharmaceuticals International Company participated in trial

design, data collection, data analysis, data interpretation, and writing of the report. The

sponsor of the study was involved in the design of the trial and provided grants to trial sites

and had no other involvement in conduct of trial. The corresponding author had full access to

all the data in the study and had final responsibility for the decision to submit for publication.

4 Dreicer_201 manuscript_28Oct2013

Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Statement of Translational Relevance

This phase 1/2 trial of orteronel tests the concept of selective inhibition of the

androgen synthesis pathway combined with continued adrenal cortisol synthesis by targeting

the 17,20-lyase activity over the 17α-hydroxylase activity of CYP17A1 in the treatment of

men with metastatic castration-resistant prostate cancer (mCRPC) and increased sensitivity

to low remaining androgens. Alleviating the effects of early castration resistance can

contribute to the development of more effective orteronel-based treatment for mCRPC. In

this trial, we conducted dose escalation studies to evaluate the clinical benefits and

pharmacokinetics of orteronel. This is the first clinical manuscript to report the safety and

efficacy of orteronel. Our findings are currently being validated in ongoing phase III trials in

patients with mCRPC.

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Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Abstract

Purpose: The androgen receptor pathway remains active in men with prostate cancer

whose disease has progressed following surgical or medical castration. Orteronel (TAK-700)

is an investigational, oral, non-steroidal, selective, reversible inhibitor of 17,20-lyase, a key

enzyme in the production of androgenic hormones.

Experimental Design: We conducted a phase 1/2 study in men with progressive,

chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) and serum

testosterone <50 ng/dL. In the phase 1 part, patients received orteronel 100–600 mg twice-

daily (BID) or 400 mg BID plus prednisone 5 mg BID. In phase 2, patients received orteronel

300 mg BID, 400 mg BID plus prednisone, 600 mg BID plus prednisone or 600 mg once-

daily without prednisone.

Results: In phase 1 (n = 26), no dose-limiting toxicities were observed and 13/20 evaluable

patients (65%) achieved ≥50% prostate-specific antigen (PSA) decline from baseline at 12

weeks. In phase 2 (n = 97), 45/84 evaluable patients (54%) achieved a ≥50% decline in PSA

and at 12 weeks, substantial mean reductions from baseline in testosterone (–7.5 ng/dL) and

dehydroepiandrosterone-sulfate (DHEA-S; –45.3 μg/dL) were observed. Unconfirmed partial

responses were reported in 10/51 evaluable phase 2 patients (20%). Decreases in

circulating tumor cells were documented. Fifty-three percent of phase 2 patients experienced

grade ≥3 adverse events irrespective of causality; most common were fatigue, hypokalemia,

hyperglycemia, and diarrhea.

Conclusions: 17,20-lyase inhibition by orteronel was tolerable and results in declines in

PSA and testosterone, with evidence of radiographic responses.

Category: Clinical Trials

ClinicalTrials.gov identifier: NCT00569153

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Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Introduction

Testosterone suppression through medical or surgical castration has been the

standard of care in advanced prostate cancer since the seminal work of Huggins and

Hodges (1). Androgen deprivation therapy, while highly effective short term, is not curative

with the majority of patients eventually developing disease progression (2).

In CRPC, intraprostatic dihydrotestosterone, and testosterone levels remain

sufficiently elevated to activate the androgen receptor (AR) despite castrate serum levels

with evidence for persistent expression of androgen-synthesising enzymes and ongoing

androgen synthesis within prostate tumors collected from castrated patients (3, 4). The most

common mechanism of early resistance is AR upregulation, which increases sensitivity to

low remaining androgens (5). These findings have fostered an interest in CYP17A1 inhibition

to deplete both intra-tumoral and extragonadal sources of steroid ligands (6, 7). CYP17A1 is

an essential enzyme for biosynthesis/production of steroidal hormones, and has both 17,20-

lyase and 17α-hydroxylase activities (8-10). This pathway’s importance in CRPC has been

reinforced by positive phase-3 trials with abiraterone acetate (Zytiga®) (11, 12) and AR

antagonist enzalutamide (Xtandi®) (13). Both agents have demonstrated increased overall

survival in patients with advanced mCRPC previously treated with docetaxel (11, 13).

Orteronel (TAK-700) is a non-steroidal, selective, reversible inhibitor of 17,20-lyase.

Five-fold selectivity of orteronel for 17,20-lyase activity over 17α-hydroxylase activity of

CYP17A1 has been demonstrated in preclinical studies (14). Orteronel may therefore result

in near full inhibition of androgen synthesis with only partial inhibition of 17α-hydroxylase

activity, allowing adrenal cortisol synthesis to continue – an important consideration as

inhibition thereof can lead to mineralocorticoid excess. Preclinical data show that orteronel

reduces and maintains low testosterone levels (14). This is the first clinical report to

characterize the safety and efficacy of orteronel, based on findings from the phase 1/2 study

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Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

in men with chemotherapy-naïve mCRPC.

Methods

Patients

Patients were recruited from 11 US centers. The study was conducted in accordance

with the Declaration of Helsinki/Good Clinical Practice, Institutional Review Boards approved

all aspects of the study, and all participants provided written informed consent. Eligibility

included pathologically confirmed prostate adenocarcinoma with radiographically-confirmed

metastatic disease progression despite castrate levels of testosterone (<50 ng/dL), an

Eastern Cooperative Oncology Group performance status of 0–2, and prostate-specific

antigen [PSA] ≥5 ng/mL. Eligibility also required adequate hematologic, cardiovascular,

renal, and hepatic function. Patients also had to be free of significant prostate cancer related

symptoms, including opioid-requiring bone pain. Patients could have received

aminoglutethimide, ketoconazole, or radiation therapy, but not within 30 days prior to first

dose of study drug.

Study design

Phase 1 dose escalation followed a standard 3+3 schema: patients received open-

label single-agent orteronel in 28-day cycles (continuous dosing) at 1 of 5 dose levels: 100,

200, 300, 400, or 600 mg twice-daily (BID). An additional cohort also received orteronel

400 mg BID plus prednisone 5 mg BID.

In phase 2, patients received open-label orteronel daily without food restrictions in

28-day cycles in four parallel dose cohorts: 300 mg BID, 400 mg BID plus prednisone 5 mg

BID, 600 mg BID plus prednisone 5 mg BID, or 600 mg once-daily (QD) in the morning.

These regimens were selected for further exploration based on 1) frequency of PSA

responses at doses ≥300 mg BID; 2) the determination that any dose regimen ≥400 mg BID

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Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

would likely benefit from concomitant prednisone administration; and 3) to test whether

administration of 600 mg QD was similarly efficacious to an equal but divided daily dose.

Patients continued to receive orteronel until PSA progression (prostate cancer

working group 2 [PCWG2](15)), objective disease progression by Response Evaluation

Criteria in Solid Tumors (RECIST) (16), bone scan or investigator opinion, or occurrence of

unacceptable toxicity. At investigator assessment and request, patients with PSA

progression without new symptoms were allowed to remain on study drug.

The primary objective was to assess safety and tolerability. Secondary objectives

included assessment of efficacy, as shown by PSA response and/or objective disease

response; assessment of endocrine responses to orteronel (testosterone,

dehydroepiandrosterone-sulfate [DHEA-S] and adrenocorticotropic hormone (ACTH)-adrenal

axis; pharmacodynamics); and pharmacokinetics of orteronel. Exploratory objectives

included enumeration of circulating tumor cells (CTCs).

Assessments

Sampling timepoints are shown in Supplemental Table 1. Adverse events (AEs) were

graded using National Cancer Institute Common Terminology Criteria for Adverse Events

(NCI-CTCAE) v3.0. During phase 1, maximum tolerated dose (MTD) was defined as the

dose level immediately below that at which ≥2 of up to 6 patients experienced dose limiting

toxicities (DLTs) in cycle 1. DLTs were defined as any drug-related grade ≥3 AE or any

cardiac-related AE. Documented fatigue events were based on CTC criteria and not a formal

patient reported outcome; thus, mechanism of fatigue (CNS central vs. neuromuscular)

requires additional study. Pharmacokinetic parameters were determined from plasma

concentration-time data using standard noncompartmental methods.

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Radiologic response was assessed according to modified RECIST v1.0, with

non-confirmation per RECIST v1.1. Bone scan progression was assessed per RECIST

rather than per PCWG2 criteria, which came into practice after the initiation of this study.

The endocrine and cortisol assays in phases 1 and 2, respectively, were performed at

different laboratories using assays with different lower limits of quantification. In phase 2 and

in phase 1 patients ongoing after the start of phase 2, liquid chromatography/mass

spectrometry (LC/MS) was used for evaluation of testosterone, DHEA-S, and other steroid

hormones, except cortisol. The validated LC/MS testosterone assay was performed by

Esoterix Laboratories (LabCorp); between different laboratories, the lower limits of detection

varied during the study between 50 and 200 pg/mL (0.05–0.2 ng/dL), and results below 0.2

ng/dL should be interpreted with caution.

CTCs were enumerated using validated Veridex CellSearch® methodology (17). CTC

counts were assessed as both dichotomous (<5 vs. ≥5 per 7.5 mL of whole blood) and

quantitative variables (18, 19).

Statistical methods

Planned enrolment was up to 123 patients: up to 35 in phase 1 and 88 (22 per dose

group) in phase 2 to give 20 response-evaluable patients per group. The phase 2 portion

had 85% power and a one-sided significance of 0.05 for each BID dose group to detect a

50% PSA response (PSA50) rate at 12 weeks versus 20% for null hypothesis. The 600 mg

QD group, added later to evaluate potential differences versus 300 mg BID, had 80% power

to detect a PSA50 response. Phase-1 patients treated at dose levels also evaluated in the

phase 2 component of the trial were included in the phase-2 analysis.

Standard summary statistics were used for PSA and endocrine changes over time,

as well as for observed values and change from baseline in CTCs. Time to disease

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Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

progression (duration from the date of first dose until the date of the first documented

evidence of progressive disease) was analyzed using Kaplan-Meier methodology.

Results

Patients

Twenty-six patients were enrolled in the phase 1 portion of the study and, due to

slight over-enrolment, 97 in the phase 2 portion. Enrollment commenced on April 2, 2008

and the last patient completed 6 months of treatment on March 15, 2011. Baseline

demographics and patient characteristics are shown in Table 1.

Phase 1 patients received a median of 7 (range 0–36) 28-day treatment cycles. 22

patients (85%) have discontinued therapy due to: AEs in 8 patients, objective disease

progression in 7, PSA progression in 3, voluntary withdrawal in 3, and other reasons in 1.

Four patients remain on therapy (1 each at 200, 300, 600 mg BID, and 400 mg BID plus

prednisone) with a maximum duration of 1030 days’ treatment (>36 cycles). Phase-2

patients completed a median of 9 (range 0–22) treatment cycles. At the time of analysis, 37

patients remained on treatment, with a maximum duration of 638 days’ treatment in a patient

receiving 400 mg BID plus prednisone (>22 cycles); as of April, 2013, 6 patients are

ongoing. Sixty patients (62%) discontinued treatment due to: AE (n = 18, of which 11 were

considered drug-related), objective disease progression (n = 18), PSA progression (n = 12),

voluntary withdrawal (n = 11), and other (n = 1).

Phase 1: Dose escalation and DLTs

During dose escalation, there were no DLTs and an MTD was not established;

however, at 600 mg BID, 3 of 5 patients experienced severe non-dose limiting (grade 3)

fatigue. All 3 patients were aged ≥80 years, and consequently, patients ≥80 years were

excluded from the 600 mg BID plus prednisone cohort in the phase 2 portion. For phase 2,

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Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

prednisone 5 mg BID was added to the 400 mg BID or 600 mg BID dose regimens. The

decision to not further test steroid-free dosing at those levels was based on ACTH and

associated endocrine data which indicated increased risk for mineralocorticoid excess, as

well as symptoms such as fatigue that may have been associated with (delayed) adrenal

adaptation to 17α-hydroxylase inhibition. Other phase 2 cohorts were 300 mg BID (n = 23),

600 mg QD (n = 24), and 400 mg BID plus prednisone (n = 24).

Safety

In phase 1, all patients experienced ≥1 treatment-emergent AE (TEAE) and 96%

drug-related TEAEs (Table 2). In phase 2, all but 1 patient had a TEAE; most common were

fatigue (77%), nausea (47%), constipation (37%), and diarrhea (35%). Grade ≥3 AEs were

experienced by 51 patients (53%); most common were fatigue (12%), hypokalemia (8%),

hyperglycemia (5%), and diarrhea (4%). Drug-related AEs were reported in 97% of patients

(Table 2). Two grade 3 hepatic transaminase ‘investigations’ AEs were reported (per NCI-

CTCAE); however, there were no patient discontinuations related to hepatic abnormalities.

Serious AEs (SAEs) were experienced by 8 (31%) and 26 (27%) patients in phases 1

and 2, respectively, and were drug-related in 5 and 7 patients. Drug-related SAEs in phase 1

were hypertension, nausea, vomiting, deep vein thrombosis (DVT), fatigue, increased

amylase, increased lipase, diarrhea, skin infection, and dehydration (each n = 1); in patients

receiving orteronel 400 mg BID plus prednisone, one drug-related SAE of vomiting was

reported. SAEs related to single-agent orteronel in phase 2 were fatigue (n = 1) and

hypertension (n = 1); in patients receiving orteronel plus prednisone, drug-related SAEs of

acute renal failure, hypokalemia (each n = 2), pneumonia, decreased hemoglobin,

hyperglycemia, hyperkalemia, pain in extremity, sensory neuropathy, and DVT (each n = 1)

were reported.

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As described above, while significant fatigue occurred in older patients receiving 600

mg BID without prednisone, overall there was no overt evidence of clinical ACTH-adrenal

insufficiency in the phase 1 patients receiving steroid-free dose regimens. This is

presumably due compensatory ACTH-driven increased levels of mineralocorticoids with

intrinsic glucocorticoid activity, predominantly corticosterone.

There were 3 on-study deaths all in the phase 2 portion; all deaths were considered

unrelated to study drug: cardiac-related events (n = 2, 600 mg QD) and infection (400 mg

BID plus prednisone).

Pharmacokinetics

Mean orteronel plasma concentrations in cycle 1, day 8 (phase 1) following the

morning dose are shown in Fig. 1. Pharmacokinetic analysis indicates dose-related

increases in single- and multiple-dose Cmax and AUC0–8h over the 100–600 mg BID dose

range. Fasting at the time of dosing was not required.

Endocrine pharmacodynamics

Pharmacodynamic analysis in phase-1 patients showed androgen suppression.

DHEA-S levels decreased to below quantifiable levels (assays sensitive to 15 μg/dL) in all

patients receiving orteronel ≥300 mg BID. Testosterone levels decreased to <10 ng/dL in all

patients receiving orteronel ≥300 mg BID (local laboratory assays sensitive to 10 ng/dL).

In phase 2, androgen suppression occurred by cycle 1, day 15, and responses were

maximal by cycle 2, day 1. At 12 weeks, substantial mean reductions in testosterone (–7.5

ng/dL [standard deviation {SD}: 5.14]) and DHEA-S (–45.3 μg/dL [SD: 40.26]) were

observed from baseline (Fig. 2). At 12 weeks, 46% of patients (45 of 97) achieved

testosterone <1 ng/dL and 54% and 32% of patients had DHEA-S levels <10 μg/dL or <1

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Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

μg/dL, respectively. The most profound reductions occurred in the 400 mg and 600 mg BID

plus prednisone dose groups.

For phase 2, the ACTH-adrenal axis was evaluated using measurements of ACTH,

cortisol, and corticosterone. The normal range for ACTH is 9–52 pg/mL (20) and in patients

receiving orteronel 400 mg and 600 mg BID plus prednisone, the ACTH-adrenal axis was

effectively suppressed, with ACTH and cortisol levels reduced relative to baseline (Fig. 2). In

the 300 mg BID dose group, mean ACTH levels increased post baseline combined with

modest decreases in cortisol (baseline: 11–15 μg/dL; cycle 4: 3–10 μg/dL) and increased

corticosterone.

Clinical response

In phase 1, orteronel ≥300 mg was associated with decreases in PSA levels. Overall,

13 of 20 evaluable patients (65%) had ≥50% decreases in PSA at 12 weeks.

At 12 weeks, PSA was evaluable in 84 phase-2 patients (Fig. 3A). Forty-five of 84

evaluable patients (54%) had ≥50% decline in PSA from baseline and 18 (21%) had ≥90%

decline in PSA. At 24 weeks, a ≥50% decrease in PSA occurred in 37 of 59 evaluable

patients (63%) and 17 (29%) of the 59 evaluable patients who remained on study treatment

had ≥90% decline in PSA (Fig. 3B). Time to PSA progression is shown in Fig. 3C; the

Kaplan-Meier estimated median was >225 days in all 4 dose groups.

Prior adrenal-directed therapy (predominantly ketoconazole; abiraterone acetate in 4

patients) appeared to be associated with a lower likelihood of a obtaining a ≥50% decrease

in PSA at 12 weeks, with only 12 of 33 patients (36%) with prior adrenal-directed therapy

reaching this threshold, compared with 46 of 71 (65%) who had not received prior adrenal-

directed therapy.

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Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Fifty-one of 97 phase-2 patients (53%) had RECIST-evaluable radiographic lesions.

Unconfirmed RECIST partial responses were observed in 10 of 51 evaluable patients (20%;

Table 3), and 21 (41%) had stable disease. Radiographic disease progression was reported

in 16 patients.

CTC analyses

At baseline, the mean overall CTC count was 16.6/7.5 mL whole blood (SD: 33.2)

among 88 evaluable patients. By 12 weeks, mean overall CTC counts had fallen to 3.9/7.5

mL (SD: 11.2) and the mean change in CTCs (baseline to week 12) was –76·5%.

Of 63 patients with evaluable CTC counts at both baseline and 12 weeks, 14 (22%)

converted to a favorable CTC count and 36 (57%) retained a CTC count of <5 at 12 weeks.

Discussion

Findings of this clinical study demonstrate for the first time that selective inhibition of

17,20-lyase with orteronel with/without prednisone, and given without food requirement,

results in PSA and radiographic responses with declines in CTCs in men with mCRPC.

Pharmacokinetic data demonstrate a dose-dependent relationship that is stable over time.

Although the study was not powered to compare doses, the two higher phase 2 doses with

prednisone were most effective in lowering testosterone and DHEA-S levels. ACTH and

corticosterone levels were modestly increased in the steroid-free regimens while relatively

suppressed in the prednisone-supplemented groups. A more detailed analysis of the

orteronel endocrine profile has been reported (21).

Orteronel was generally well tolerated with AEs that were predictable based upon the

proposed mechanism of action and co-administration with prednisone; the median orteronel

15 Dreicer_201 manuscript_28Oct2013

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treatment duration of 7–9 months is consistent with the overall pattern of maintained disease

stability combined with adequate toleration. Grade ≥3 AEs were experienced by 51 phase-2

patients (53%); most common were fatigue, hypokalemia, diarrhea, and hyperglycemia. No

DLTs were observed during phase 1. However, severe fatigue (grade 3) occurred in 3 older

patients treated with 600 mg BID without prednisone. Isolated events of prolonged QT-

interval were reported, but there was no relationship to orteronel dose or concentrations and

overall across groups there were no directional changes in any ECG interval parameters.

The absence of a dose response for the observed common AEs in this study makes it

difficult to judge their specific relationship to orteronel administration.

The phase 1 dose escalation data, combined with the phase 2 endocrine data,

measured using more sensitive assays, together support that orteronel has selectivity for

17,20-lyase versus 17α-hydroxylase. At 300 mg BID, orteronel reduced testosterone

concentrations by ≥90% in most patients, without clinically relevant inhibition of the ACTH-

cortisol axis. At higher doses, some evidence of 17α-hydroxylase inhibition was apparent. In

phase 1, however, it is not clear whether the severe fatigue observed in patients ≥80 years

receiving 600 mg BID was due to delayed adaptation to 17α-hydroxylase inhibition or rather

the effects of acute more profound androgen withdrawal. Less fatigue was noted in

subsequent patients receiving either 400 mg BID or 600 mg BID plus prednisone co-

administration. However, there is no compelling evidence to support the exclusion of men

≥80 years from therapy with orteronel.

Based on the overall phase 1 and phase 2 results, 400 mg BID plus prednisone 5 mg

BID was the dose regimen taken forward for phase 3 evaluation in both patients with

chemotherapy-naïve (NCT01193244) and post-docetaxel (NCT01193257) mCRPC.

Furthermore, as prednisone is known to have antitumor activity (22), it was thought that the

addition of prednisone might further the benefit of orteronel for men with mCRPC.

16 Dreicer_201 manuscript_28Oct2013

Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Phase-2 patients who received total doses of 600 mg daily (300 mg BID or 600 mg

QD) did not receive concomitant prednisone. Patients receiving this steroid-free regimen had

similar PSA responses and radiographic stability versus those on the higher-dose regimens.

The incidence of hypokalemia and hypertension was modestly increased in these two

groups relative to 400 mg BID plus prednisone, but overall, the steroid-free regimens were

well tolerated and did not have higher discontinuation rates. The favorable results in patients

receiving orteronel doses of 600 mg daily suggest that this agent may allow for effective

androgen synthesis inhibition without glucocorticoid supplementation. This could be of

particular benefit in patients receiving orteronel for prolonged periods or in those at

increased risk from the effects of prednisone administration due to comorbidities such as

diabetes or bone loss. The steroid-free regimen of orteronel 300 mg BID is undergoing

further evaluation in patients with progressive (rising PSA) non-mCRPC (M0) (23), as well as

phase 3 studies in earlier stages of disease (NCT01546987, NCT01707966, NCT01809691).

During the past decade, significant progress in understanding the biology of the AR

has been translated into clinically relevant therapeutic developments. Two recently approved

agents–the steroidal CYP17A1 inhibitor abiraterone acetate and the AR inhibitor

enzalutamide–have both demonstrated survival benefits over placebo in patients with

mCRPC post docetaxel (14.8 vs. 10.9 months (11) and 18.4 vs. 13.6 months (24),

respectively). In this new era of more intensive androgen synthesis inhibitors and AR-

directed therapies, the optimal timing, sequencing, pharmacoeconomics, ease of

administration, and therapy-related toxicity (e.g. effects of or requirement for co-administered

steroids and the timing of any subsequent chemotherapy) will likely drive decision making in

this clinical setting.

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Contributors

RD, DBM, YS, IA, and DBA contributed to the conception and design of the study. RD, DS,

OH, JH, MEG, and DBA contributed to the provision of study materials, patient recruitment,

or acquisition of data. RD, AS, WMS, LH, GRM, OH, YS, and DBA participated in the

collection and assembly of data. RD, DBM, AS, WMS, LH, GRM, OH, JH, MEG, YS, IA, and

DBA participated in the data analysis and interpretation. All authors participated in the draft

of the manuscript, revised it critically, and gave final approval to submit for publication.

Acknowledgments

All study sites and institutions received funding from Millennium: The Takeda Oncology

Company, Cambridge, MA, USA, to cover the expenses of the investigators,

subinvestigators, and study staff for clinical trial execution. The authors would like to thank

the patients who participated in this study and their families, as well as staff at all

investigational sites. The authors also acknowledge the contributions of Jingyuan Wang and

Laura DeLeon of Takeda Pharmaceuticals International Company for statistical and trial

management support.

The authors also acknowledge the editing assistance of Catherine Crookes of FireKite, Ltd,

during the development of this paper, which was funded by Millennium: The Takeda

Oncology Company.

18 Dreicer_201 manuscript_28Oct2013

Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

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Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Tables

Table 1. Patient demographics and disease characteristics

Phase 1 Phase 2 Characteristic (N = 26) (N = 97) Median age, years (range) 70 (46–87) 70 (49–90) Race, n (%) White 22 (85) 83 (86) Black/African American 3 (12) 8 (8) Asian 1 (4) 3 (3) Native Hawaiian/other Pacific Islander 0 1 (1) Unknown 0 2 (2) Median PSA at baseline, ng/mL (range) 57.4 (6.4–3812.0) 44.3 (5.9–820.0) Disease stage at diagnosis, n (%)* 1 2 (8) 8 (8) 2 7 (27) 14 (14) 3 4 (15) 19 (20) 4 3 (12) 15 (16) Unknown 10 (39) 39 (40) Prior adrenal-directed therapy†, n (%) 12 (46) 29 (30) Abbreviation: PSA, prostate-specific antigen. *Data missing for 2 patients in the phase 2 portion. †Aminoglutethimide, abiraterone, ketoconazole.

23 Dreicer_201 manuscript_28Oct2013

Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC Downloaded from Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited. Table 2. Most common treatment-related AEs (Reported at any grade in ≥20% or at grade ≥3 in ≥5% of phase 1 patients overall [n = 26], or Author ManuscriptPublishedOnlineFirstonJanuary13,2014;DOI:10.1158/1078-0432.CCR-13-2436

reported at any grade in ≥15% or at grade ≥3 in ≥5% of phase 2 patients overall [n = 97])

clincancerres.aacrjournals.org Orteronel alone (steroid-free) Orteronel plus prednisone Phase 1 Phase 2 Phase 2 Phase 1 Phase 2 Phase 2 100–600 mg BID 300 mg BID 600 mg QD 400 mg BID plus 400 mg BID plus 600 mg BID plus (n = 20) (n = 23) (n = 24) prednisone prednisone prednisone (n = 6) (n = 24) (n = 26) Patients with AEs, Any Grade ≥3 Any grade Grade ≥3 Any grade Grade ≥3 Any Grade ≥3Any Grade ≥3 Any Grade ≥3 n (%) grade grade grade grade Any drug-related AE 19 (95) 11 (55) 23 (100) 8 (35) 24 (100) 4 (17) 6 (100) 2 (33) 22 (92) 8 (33) 25 (96) 10 (39) Fatigue 15 (75) 3 (15) 17 (74) 1 (4) 18 (75) 3 (13) 2 (33) 1 (17) 16 (67) 3 (13) 20 (77) 4 (15) Nausea 9 (45) 1 (5) 10 (44) – 8 (33) – 1 (17) – 10 (42) – 15 (58) 2 (8) Headache 8 (40) – 9 (39) – 4 (17) – 1 (17) – 7 (29) – 2 (8) – on September 28, 2021. © 2014American Association for Cancer Constipation 6 (30) – 7 (30) – 5 (21) – 3 (50) – 6 (25) – 11 (42) – Research. Diarrhea 4 (20) 3 (15) 7 (30) 1 (4) 5 (21) 1 (4) 1 (17) – 6 (25) 1 (4) 7 (27) – Anorexia 9 (45) – 5 (22) – 3 (13) – 1 (17) – 6 (25) – 8 (31) 1 (4) Dizziness 2 (10) – 5 (22) – 2 (8) – 2 (33) – 4 (17) – 7 (27) – Hot flush 2 (10) – 4 (17) – 1 (4) – 1 (17) – 4 (17) – 6 (23) – Hypokalemia 2 (10) – 4 (17) 2 (9) 2 (8) – – – 1 (4) 1 (4) 3 (12) 3 (12) Muscle spasms – – 4 (17) – 2 (8) – 1 (17) – 5 (21) – 6 (23) – Vomiting 6 (30) 1 (5) 2 (9) – 3 (13) – 1 (17) 1 (17) 1 (4) – 1 (4) 1 (4) Prolonged QT interval 5 (25) 1 (5) 4 (17) – 1 (4) – 1 (17) – 1 (4) – – – Hyperglycemia 1 (5) – 4 (17) 1 (4) 3 (13) – 1 (17) – 4 (17) 1 (4) 4 (15) 1 (4) Hypertension 6 (30) 2 (10) 5 (22) – 1 (4) – – – 2 (8) – 5 (19) 1 (4) Lymphopenia 6 (30) 2 (10) 3 (13) 1 (4) 1 (4) – – – 2 (8) – 2 (8) 1 (4) Increased lipase 2 (10) 2 (10) – – – – – – – – – – Any drug-related SAE 4 (20) – 1 (4) – 1 (4) – 1 (17) – 2 (8) – 3 (12) – Abbreviations: AEs, adverse events; BID, twice-daily; [LV]EF, left ventricular ejection fraction; QD, once-daily; SAE, serious AEs. Discontinuations due to drug-related AEs in phase 2 were fatigue (n = 3), decreased performance status (n = 1), diarrhea (n = 2), nausea (n = 1), [LV]EF dysfunction (n = 2), somnolence (n = 1), acute renal failure (n = 1), dyspnea (n = 1), maculopapular rash (n = 1); and due to all- cause AEs were edema (n = 1), respiratory arrest (n = 1), spinal cord compression (n = 1), bacteraemia (n = 1), supraventricular extrasystoles (n = 1), arthralgia (n = 1), pain (n = 1), meningioma (n = 1).

24 Dreicer_201 manuscript_28Oct2013

Author Manuscript Published OnlineFirst on January 13, 2014; DOI: 10.1158/1078-0432.CCR-13-2436 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Table 3. Objective disease response by RECIST (phase 2*)

Orteronel alone (steroid-free) Orteronel plus prednisone 400 mg BID 600 mg BID plus plus Patients, n (%) 300 mg BID 600 mg QD prednisone prednisone Overall Best response by RECIST Evaluable patients n = 12 n = 12 n = 10 n = 17 N = 51 Complete response 0 0 0 0 0 PR 4 (33) 2 (17) 2 (20) 2 (12) 10 (20) SD 4 (33) 5 (42) 6 (60) 6 (35) 21 (41) PR or SD 8 (67) 7 (58) 8 (80) 8 (47) 31 (61) Progressive disease 4 (33) 4 (33) 1 (10) 7 (41) 16 (31) Abbreviations: BID, twice-daily; PR, partial response; QD, once-daily; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease. *Phase 1 patients treated at the same dose levels as phase 2 are included in this analysis.

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Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC

Figure Legends

Figure 1. Mean plasma orteronel concentrations (phase 1) following the morning dose of

orteronel on day 8 of cycle 1

Abbreviation: BID, twice-daily.

Figure 2. Effect of orteronel on A, testosterone, B, DHEA-S, C, ACTH, and D, corticosterone

levels (phase 2)

Abbreviations: ACTH, adrenocorticotropic hormone; BID, twice-daily; DHEA-S,

dehydroepiandrosterone-sulfate; QD, once-daily.

Figure 3. Percent change in PSA at A, 12 weeks, and B, 24 weeks by dose group and prior

ketoconazole therapy (phase 2), and C, phase 2 Kaplan-Meier plot for time to PSA

progression

Abbreviations: BID, twice-daily; PSA, prostate-specific antigen; QD, once-daily

26 Dreicer_201 manuscript_28Oct2013

Phase 1/2 Trial of Orteronel (TAK-700) - an Investigational 17,20-Lyase Inhibitor - in Patients with Metastatic Castration-Resistant Prostate Cancer

Robert Dreicer, David MacLean, Ajit Suri, et al.

Clin Cancer Res Published OnlineFirst January 13, 2014.

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