Study Comparing Orteronel Plus Prednisone in Participants With Metastatic Castration-Resistant Prostate Cancer.

A Phase 3, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel (TAK-700) Plus Prednisone With Placebo Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer That Has Progressed During or Following Docetaxel-based Therapy.

This is a randomized, double-blind, multicenter, phase 3 study evaluating orteronel plus prednisone compared with placebo plus prednisone in men with metastatic, castration-resistant prostate cancer (mCRPC) that has progressed following Docetaxel-based therapy

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Prednisone; Drug: Orteronel; Drug: Orteronel Placebo

• Study Type: Interventional
• Enrollment (Actual): 1099
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Redcliffe, Queensland, Australia
  • South Australia
    • Woodville South, South Australia, Australia, 5011
  • Tasmania
    • Hobart, Tasmania, Australia
  • Victoria
    • Malvere, Victoria, Australia
    • Wodonga, Victoria, Australia
• Belgium
  • Brussels, Belgium
  • Kortijk, Belgium
  • Liege, Belgium
  • Namur, Belgium
• Canada
  • Alberta
    • Edmonton, Alberta, Canada
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y2H4
  • New Brunswick
    • Moncton, New Brunswick, Canada
  • Ontario
    • Brampton, Ontario, Canada, L6T4S5
    • Newmarket, Ontario, Canada
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V2H3
    • Montreal, Quebec, Canada
    • Pointe-Claire, Quebec, Canada, H9R4S3
• Czechia
  • Hradec Dralove, Czechia
  • Kromertz, Czechia
  • Modrice, Czechia
  • Praha, Czechia
  • Zlin, Czechia
• Estonia
  • Tallinn, Estonia
• Finland
  • Oulu, Finland
  • Tampere, Finland
• France
  • La Roche-sur-Yon, France
  • Le Mans, France
  • Lyon, France
  • Lyon Cedex, France
  • Marseille, France
  • Paris, France
  • Villejuif cedex, France, 94805
• Greece
  • Patras, Greece
• Hungary
  • Miskolc, Hungary
  • Osztaly, Hungary
• Italy
  • Novara, Italy
  • Rome, Italy
• Netherlands
  • Eindhoven, Netherlands
• Poland
  • Bielsko-Biala, Poland
  • Goczalkowice-Zdroj, Poland
  • Wroclaw, Poland
• Spain
  • Sevilla, Spain
• United States
  • Alaska
    • Anchorage, Alaska, United States, 99508
  • Arkansas
    • Fort Smith, Arkansas, United States, 72903
  • California
    • Fountain Valley, California, United States, 92708
    • Los Angeles, California, United States, 90025
    • Riverside, California, United States, 92501
    • San Diego, California, United States, 92120
  • Florida
    • Fort Myers, Florida, United States, 33916
    • Port Saint Lucie, Florida, United States, 34952
  • Indiana
    • Indianapolis, Indiana, United States, 46219
    • Jeffersonville, Indiana, United States, 47130
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
  • Maryland
    • Westminster, Maryland, United States, 21157
  • Michigan
    • Detroit, Michigan, United States, 48201
  • Missouri
    • Jefferson City, Missouri, United States, 65109
  • Nevada
    • Las Vegas, Nevada, United States, 89169
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
  • New York
    • Albany, New York, United States, 12208
    • East Syracuse, New York, United States, 13057
    • Rochester, New York, United States, 14623
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
  • Ohio
    • Cincinnati, Ohio, United States, 45230
  • Oregon
    • Tualatin, Oregon, United States, 97062
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17604
    • Pittsburgh, Pennsylvania, United States, 15212
  • South Carolina
    • Greenville, South Carolina, United States, 29605
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
    • Nashville, Tennessee, United States, 37203
  • Texas
    • Amarillo, Texas, United States, 79106
    • Bedford, Texas, United States, 76022
    • Dallas, Texas, United States, 75246
    • Dallas, Texas, United States, 75231
    • Odessa, Texas, United States, 79761
    • Tyler, Texas, United States, 75702
    • Webster, Texas, United States, 77598
  • Utah
    • Salt Lake City, Utah, United States
  • Virginia
    • Newport News, Virginia, United States, 23606
  • Washington
    • Kennewick, Washington, United States, 99336

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

Each participant must meet all of the following inclusion criteria:

• Voluntary written consent
• Male 18 years or older
• Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma
• Radiograph-documented metastatic disease
• Progressive disease
• Prior surgical castration or concurrent use of an agent for medical castration
• Progressive disease during or following 1 or 2 regimens of cytotoxic chemotherapy, 1 of which must have included docetaxel. Must have received greater than or equal to (>=) 360 milligram per square meter (mg/m^2) of docetaxel within a 6-month period. Participants who were clearly intolerant to docetaxel or develop progressive disease before receiving >= 360 mg/m^2 are also eligible if they have received at least 225 mg/m^2 of docetaxel within a 6-month period and meet the other study entry criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• Even if surgically sterilized, participants must practice effective barrier contraception during the entire study treatment period and for 4 months after the last dose of study drug, OR Abstain from heterosexual intercourse
• Screening laboratory values as specified in protocol
• Stable medical condition
• Life expectancy of 6 months or more
• Participants who have had up to 2 prior chemotherapy treatments are eligible to participate

Exclusion Criteria:

Participants meeting any of the following exclusion criteria are not to be enrolled in the study:

• Known hypersensitivity to orteronel, prednisone or gonadotropin-releasing hormone (GnRH) analogue
• Received prior therapy with orteronel, aminoglutethimide, ketoconazole or abiraterone
• Any other therapies for prostate cancer, except for GnRH analogue therapy, must be discontinued 2 weeks before the first dose of study drug
• Radioisotope therapy or external beam radiation therapy within 4 weeks of first dose of study drug
• Documented central nervous system metastases
• Treatment with any investigational compound within 30 days prior to first dose of study drug (Participants who are in long-term follow-up following active treatment in other trials are eligible)
• Diagnosis or treatment of another malignancy within 2 years preceding first dose of study drug except nonmelanoma skin cancer or in situ malignancy completely resected
• Uncontrolled cardiovascular condition as specified in study protocol
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
• Unwilling or unable to comply with protocol
• Known gastrointestinal disease or procedure that could interfere with oral absorption or tolerance of orteronel
• Uncontrolled nausea, vomiting, or diarrhea despite appropriate medical therapy
• Prostate cancer confined to just the prostrate bed or immediate adjacent tissue

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Orteronel + prednisone	Drug: Prednisone; Prednisone tablets; Drug: Orteronel; Orteronel tablets; Other Names: TAK-700
Placebo Comparator: Placebo + prednisone	Drug: Prednisone; Prednisone tablets; Drug: Orteronel Placebo; Orteronel placebo-matching tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival was calculated from the date of participant randomization to the date of participant death due to any cause. Participants without documentation of death at time of the analysis were censored as of the date the participant was last known to be alive, or the data cutoff date, whichever was earlier.	Baseline until death (approximately up to 4.5 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiographic Progression-free Survival (rPFS)	rPFS was defined as the time from randomization until radiographic disease progression or death due to any cause, whichever occurred first. Radiographic disease progression was defined as the occurrence of 1 or more of the following: The appearance of 2 or more new lesions on radionuclide bone scan as defined by prostate cancer working group (PCWG)2; Should 2 or more new bone lesions be evident at the first assessment (8-week assessment) on treatment, 2 or more additional new lesions must have been evident on a confirmatory assessment at least 6 weeks later; One or more new soft tissue/visceral organ lesions identified by computed tomography (CT)/magnetic resonance imaging (MRI); Progression as defined by response evaluation criteria in solid tumors (RECIST) 1.1 criteria.	Baseline until disease progression or death, whichever occurred first (approximately up to 4.5 years)
Percentage of Participants Achieving 50 Percent Reduction From Baseline in Prostate Specific Antigen (PSA50 Response) at Week 12	The PSA50 was defined as the percentage of participants who had a PSA decline of at least 50 percent (%) from baseline.	Week 12
Percentage of Participants With Pain Response at Week 12	Pain response was defined as the occurrence of 1 of the following and confirmed by an additional assessment, at least 3 weeks but not more than 5 weeks later: A greater than or equal to (>=) 2 point reduction from baseline in BPI-SF worst pain score without an increase in analgesic use; or a 25 percent (%) or more reduction in analgesic use from baseline without an increase in worst pain score from baseline.	Week 12
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)		Baseline up to 30 days after last dose of study drug (Cycle 59 Day 58)
Number of Participants With Abnormal Physical Examination Findings		Baseline up to 30 days after last dose of study drug (Cycle 59 Day 58)
Number of Participants With TEAEs Related to Vital Signs		Baseline up to 30 days after last dose of study drug (Cycle 59 Day 58)
Number of Participants With TEAEs Related to Weight		Baseline up to 30 days after last dose of study drug (Cycle 59 Day 58)
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status	ECOG assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours [hrs]), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead. Worst change was defined as the worst overall change that occurred in ECOG status at any measured time point during the treatment period.	Baseline up to End-of-treatment (EOT) (Cycle 59 Day 58)
Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings		Cycle 59 Day 58
Number of Participants With TEAEs Categorized Into Investigations Related to Chemistry, Hematology or Steroid Hormone Panel		Baseline up to 30 days after last dose of study drug (Cycle 59 Day 58)
Percentage of Participants Achieving PSA50 Response at Any Time During the Study	The PSA50 was defined as the percentage of participants who had a PSA decline of at least 50% from baseline.	Cycle: 4, 7, 10, 13, 16, 19, 22, and 25
Percentage of Participants Achieving 90 Percent Reduction From Baseline in Prostate Specific Antigen (PSA90 Response) at Week 12	The PSA90 was defined as the percentage of participants who had a PSA decline of at least 90% from baseline.	Week 12
Percentage of Participants Achieving PSA90 Response at Any Time During the Study	The PSA90 was defined as the percentage of participants who had a PSA decline of at least 90% from baseline.	Cycle: 7, 10, 13, 16, 19, 22, and 25
Best PSA Response at Any Time During the Study	The PSA50 was defined as the percentage of participants who had a PSA decline of at least 50% from baseline. PSA90 was defined as the percentage of participants who had a PSA decline of at least 90% from baseline.	Cycle: 4, 7, 10, 13, 16, 19, 22, and 25
Time to PSA Progression	Time to PSA progression was defined as time from randomization to a PSA increase of 25% and PSA rise of at least 2 nanogram per milliliter (ng/mL) above the lowest value observed post baseline or, if no PSA decline occurred post baseline, above the baseline PSA.	Baseline until the final on treatment assessment or until end of short term follow-up following discontinuation of treatment, whichever occurred later (approximately up to 4.5 years)
Number of Participants With Shifts From Baseline Between Favorable and Unfavorable Categories in Circulating Tumor Cell Count (CTC)	A favorable CTC count was defined as less than (<) 5 counts per (/) 7.5 mililiter (mL) in whole blood. An unfavorable CTC count was defined as >=5 counts/7.5 mL in whole blood.	Baseline and EOT (Cycle 59 Day 58)
Percentage of Participants With Objective Response	Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1. The overall objective response was defined as a complete response (CR) or partial response (PR). A complete response (CR) was defined as the disappearance of all target lesions determined by computerized tomography (CT) or MRI. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to <10 millimetre (mm). A PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of longest diameters of non-lymph node lesions and of the short diameter(s) or short axis of lymph nodes.	Baseline until disease progression or death, whichever occurred first (approximately up to 4.5 years)
Time to Pain Progression	Time to pain progression was defined as the time from participant randomization to the first assessment date of pain progression. Pain progression was defined as the occurrence of 1 of the following and confirmed by an additional assessment, at least 3 weeks but not more than 5 weeks later: The brief pain inventory-short form (BPI-SF) worst pain score was >= 4 with a >= 2 point increase over baseline in BPI-SF worst pain score with stable or increased analgesic use; The BPI-SF worst pain score was >= 4 but not less than baseline with new or increased (relative to baseline) Step II or Step III analgesic use; The BPI-SF worst pain score was <= 3 but not less than baseline with new or increased (relative to baseline) Step III analgesic use.	Baseline until EOT visit or until end of short term follow-up, whichever occurred later (approximately up to 4.5 years)
Time to Pain Response	Time to pain response was defined as the time from randomization until first pain response. Pain response was defined as the occurrence of 1 of the following and confirmed by an additional assessment, at least 3 weeks but not more than 5 weeks later: A >= 2 point reduction from baseline in BPI-SF worst pain score without an increase in analgesic use, or a 25% or more reduction in analgesic use from baseline without an increase in worst pain score from baseline. The analysis was performed by Kaplan-Meier method.	Baseline until disease progression or death, whichever occurred first (approximately up to 4.5 years)
Number of Participants With Best Pain Response	Best pain response was evaluated in participants who had a pain response across the entire study were summarized by treatment group. The pain response was defined as a >=2-point reduction from baseline in BPI-SF worst pain score without an increase in analgesic use, or a 25% or more reduction in analgesic use from baseline without an increase in worst pain score from baseline.	Baseline until disease progression or death, whichever occurred first (approximately up to 4.5 years)
Percentage of Participants With Health-related Quality of Life (HRQOL) Response at Week 12	The global health status or quality of life (QOL) was measured as the HRQOL response rate at 12 weeks using the 2-item global health status index of the european organization for research and treatment of cancer-quality of life questionnaire-C30 (EORTC QLQ-C30) instrument. HRQOL response was defined as a 17-point increase from the baseline assessment on the QOL index, after the score had been linearly transformed to a 0 to 100 scale. EORTC QLQ-C30: included 5 functional scales (physical, role, cognitive, emotional, and social), 1 global health status, 3 symptom scales (fatigue, pain, nausea/vomiting) and 6 single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score representing better level of functioning or greater degree of symptoms.	Week 12

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Heller G, McCormack R, Kheoh T, Molina A, Smith MR, Dreicer R, Saad F, de Wit R, Aftab DT, Hirmand M, Limon A, Fizazi K, Fleisher M, de Bono JS, Scher HI. Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials. J Clin Oncol. 2018 Feb 20;36(6):572-580. doi: 10.1200/JCO.2017.75.2998. Epub 2017 Dec 22.
• Suri A, Chapel S, Lu C, Venkatakrishnan K. Physiologically based and population PK modeling in optimizing drug development: A predict-learn-confirm analysis. Clin Pharmacol Ther. 2015 Sep;98(3):336-44. doi: 10.1002/cpt.155. Epub 2015 Jul 14.
• Fizazi K, Jones R, Oudard S, Efstathiou E, Saad F, de Wit R, De Bono J, Cruz FM, Fountzilas G, Ulys A, Carcano F, Agarwal N, Agus D, Bellmunt J, Petrylak DP, Lee SY, Webb IJ, Tejura B, Borgstein N, Dreicer R. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol. 2015 Mar 1;33(7):723-31. doi: 10.1200/JCO.2014.56.5119. Epub 2015 Jan 26.

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2010
• Primary Completion (Actual): May 16, 2013
• Study Completion (Actual): February 29, 2016

Study Registration Dates

• First Submitted: August 31, 2010
• First Submitted That Met QC Criteria: August 31, 2010
• First Posted (Estimate): September 1, 2010

Study Record Updates

• Last Update Posted (Actual): December 19, 2018
• Last Update Submitted That Met QC Criteria: November 28, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: Drug therapy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisone
• Other Study ID Numbers: C21005 (Registry Identifier: NRES); 2010-018662-23 (EudraCT Number); CTR20131423 (Registry Identifier: SFDA CTR); 0991413212 (Registry Identifier: TCTIN); U1111-1181-8040 (Registry Identifier: WHO)