Orteronel in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer

• Sponsor: University of Southern California (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01866423
• Collaborator: National Cancer Institute (NCI) (NIH), Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 4
• Location: 1
• Arm: 1
• Actual Duration (Months): 33
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial studies how well orteronel works in treating patients with metastatic hormone-resistant prostate cancer. Orteronel may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Prostate; Hormone-resistant Prostate Cancer; Recurrent Prostate Cancer; Stage IV Prostate Cancer	Drug: orteronel; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the relationship between circulating tumor cell (CTC)-based androgen receptor (AR) expression level and >=-50% prostate-specific antigen (PSA) decline following 12 weeks of therapy with TAK-700 (orteronel).

SECONDARY OBJECTIVES:

1. To assess changes in PSA and CTC levels and time to PSA progression (best response, decline at 12 weeks as continuous variable, etc.) with or without prior docetaxel-based treatment.

2. To assess measurable disease response and time to radiographic disease progression for castration-resistant prostate cancer (CRPC) with or without prior docetaxel-based treatment.

3. To explore relationships between endocrine and clinical responses.

4. To confirm the safety of TAK-700 administered without prednisone in patients with metastatic CRPC.

OUTLINE: Patients receive orteronel orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Trial of TAK-700 (Also Known as Orteronel) Without Prednisone for Metastatic Castration-Resistant Prostate Cancer
• Actual Study Start Date: Oct 25, 2013
• Actual Primary Completion Date: Jul 23, 2015
• Actual Study Completion Date: Jul 26, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (orteronel) Patients receive orteronel 300 mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: orteronel; Given PO; Other Names: TAK-700 ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Androgen Receptor (AR) Protein Expression Levels in CTCs [Up to 4 weeks]

   The two-sample t-test will be used. Once association between AR protein expression levels and response is established, graphical methods such as receiver-operator curves (ROC) or more quantitative methods such as the maximal chi-square method to determine whether there might be a cut-point with either great sensitivity or great specificity (or both) for identifying a cohort with either a high or low likelihood of prostate-specific antigen (PSA) response.

2. PSA Response, Defined as Occurrence of PSA Decline to Greater Than or Equal to 50% From Baseline [At 12 weeks]

   Standard descriptive methods will be used to summarize PSA. Values will be tabulated as outlined in the Prostate Cancer Working Group 2 (PCWG2) criteria and presented as Kaplan-Meier survival curves, as appropriate.

Secondary Outcome Measures

1. Best PSA Response [Up to 24 weeks]

   Values will be tabulated as outlined in the PCWG2 criteria and presented as Kaplan-Meier survival curves, as appropriate.

2. Absolute Change in PSA [Baseline to 24 weeks]

   Values will be tabulated as outlined in the PCWG2 criteria and presented as Kaplan-Meier survival curves, as appropriate.

3. Overall Response Rate Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and PCWG2 Criteria [Up to 3 years]

   Response will be tabulated descriptively with 95% confidence intervals (CIs) and Kaplan-Meier survival curves, as appropriate.

4. Duration of Response Using RECIST Version 1.1 and PCWG2 Criteria [Up to 3 years]

   Response will be tabulated descriptively with 95% CIs and Kaplan-Meier survival curves, as appropriate.

5. Number of Participants With Grade 3 or Higher Toxicity [30 days]

   Summary of grade 3 (per Common Terminology Criteria for Adverse Events (CTCAE v4.0) or higher toxicities which generally is described as a severe reaction or symptom.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the prostate

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care

• Patients, even if surgically sterilized (i.e., status post vasectomy), who agree to practice effective barrier contraception during the entire study treatment period and for 4 months after the last dose of study drug, or

• Agree to completely abstain from intercourse

• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be =< 2.5 x the upper limit of normal (ULN)

• Total bilirubin =< 1.5 x ULN

• Estimated creatinine clearance using the Cockcroft-Gault formula must be > 40 mL/minute

• Absolute neutrophil count (ANC) >= 1500 cells/microliter

• Platelet count >= 100,000 cells/microliter

• Testosterone < 50 ng/dL

• Screening calculated ejection fraction of >= 50% by multiple gated acquisition (MUGA) scan or echocardiogram; metastatic progression on primary androgen-deprivation therapy (medical or surgical castration)

• Progression requiring a change in oncologic therapy defined by any of the following:

• Radiographic progression: appearance or increase in measurable lesions on cross-sectional imaging or appearance of one or more new lesions on bone scan * Rising PSA (>= 2 ng/ml) which has risen on two occasions >= 1 week apart

• Clinical progression evidenced by increased pain or other cancer-related symptoms

• Patients should have recovered from prior oncologic therapies to a Common Terminology Criteria (CTC) grade =< 1 except stable neuropathy or alopecia at National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade =< 2; if rapid clinical progression is documented by imaging, changes in PSA, or symptoms, then study treatment can begin >= 2 weeks from prior therapy; otherwise, the following time periods between prior anti-cancer therapies and study treatment day 1 will apply:

• = 3 weeks for prior cytotoxic therapies

• = 4 weeks for flutamide or nilutamide

• = 6 weeks for bicalutamide

• = 6 weeks since bone targeted radiopharmaceutical (e.g. samarium-153, radium-223)

• Gonadotropin-releasing hormone (GnRH) agonists (leuprolide acetate, goserelin, etc.) or antagonists (degarelix, etc.) should be continued in patients without surgically-induced castrate androgen levels

• For chemotherapy naïve castration-resistant prostate cancer who are moderately symptomatic or who have hepatic metastasis: subjects must not be a candidate for docetaxel-based chemotherapy.

Exclusion Criteria:

• History of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of grade > 2 (NCI CTCAE, version 4), thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (e.g. pericardial effusion, restrictive cardiomyopathy) within 6 months prior to first dose of study drug; chronic stable atrial fibrillation on stable anticoagulant therapy is allowed

• New York Heart Association class III or IV heart failure

• Electrocardiogram (ECG) abnormalities of:

• Q-wave infarction, unless identified 6 or more months prior to screening

• Corrected QT (QTc) interval > 460 msec

• Patient has received other investigational drugs within 28 days before enrollment

• Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy

• Known hypersensitivity to compounds related to TAK-700 or to TAK-700 excipients

• Uncontrolled hypertension despite appropriate medical therapy (blood pressure [BP] of greater than 160 mmHg systolic and 90 mmHg diastolic at 2 separate measurements no more than 60 minutes apart during the screening visit); Note: patients may be rescreened after adjustment of antihypertensive medications

• Known active chronic hepatitis B or C, life-threatening illness unrelated to cancer, or any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with participation in this study

• Likely inability to comply with the protocol or cooperate fully with the investigator and site personnel

• Known gastrointestinal (GI) disease or GI procedure that could interfere with the GI absorption or tolerance of TAK-700, including difficulty swallowing tablets

• Prior treatment with >= 3 lines of cytotoxic chemotherapy for metastatic prostate cancer

• Prior treatment with TAK-700

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033

Sponsors and Collaborators

• University of Southern California
• National Cancer Institute (NCI)
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Mitchell Gross, University of Southern California

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Southern California
• ClinicalTrials.gov Identifier: NCT01866423
• Other Study ID Numbers: 4P-13-1; NCI-2013-01013; IISR-2012-M000668; P30CA014089
• First Posted: May 31, 2013
• Last Update Posted: Aug 31, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

Participant Flow

Recruitment Details	Participants were recruited at the University of Southern California (USC) medical clinics from December 2013 to February 2014. Due to results of two phase III clinical trials in metastatic, castration resistant prostate cancer (mCRPC), the sponsor determined that the drug has not demonstrated a clinical profile sufficient to move forward in mCRPC.
Pre-assignment Detail	The trial had no pre-assignment criteria. All subjects were given the same treatment.

Arm/Group Title	Treatment (Orteronel)
Arm/Group Description	Patients receive orteronel 300 mg PO BID (twice a day) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. orteronel: Given PO laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	4
COMPLETED	0
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Treatment (Orteronel)
Arm/Group Description	Patients receive orteronel 300 mg PO twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. orteronel: Given PO laboratory biomarker analysis: Correlative studies
Overall Participants	4
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 25%
>=65 years	3 75%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	4 100%
Region of Enrollment (Count of Participants)
United States	4 100%

Outcome Measures

1. Primary Outcome

Title	Androgen Receptor (AR) Protein Expression Levels in CTCs
Description	The two-sample t-test will be used. Once association between AR protein expression levels and response is established, graphical methods such as receiver-operator curves (ROC) or more quantitative methods such as the maximal chi-square method to determine whether there might be a cut-point with either great sensitivity or great specificity (or both) for identifying a cohort with either a high or low likelihood of prostate-specific antigen (PSA) response.
Time Frame	Up to 4 weeks

Outcome Measure Data

Analysis Population Description

Only 4 patients were accrued to this trial. No data analysis was performed.

Arm/Group Title	Treatment (Orteronel)
Arm/Group Description	Patients receive orteronel 300 mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. orteronel: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

2. Primary Outcome

Title	PSA Response, Defined as Occurrence of PSA Decline to Greater Than or Equal to 50% From Baseline
Description	Standard descriptive methods will be used to summarize PSA. Values will be tabulated as outlined in the Prostate Cancer Working Group 2 (PCWG2) criteria and presented as Kaplan-Meier survival curves, as appropriate.
Time Frame	At 12 weeks

Outcome Measure Data

Analysis Population Description

Only 4 patients were accrued to this trial. No data analysis was performed.

Arm/Group Title	Treatment (Orteronel)
Arm/Group Description	Patients receive orteronel 300 mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. orteronel: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

3. Secondary Outcome

Title	Best PSA Response
Description	Values will be tabulated as outlined in the PCWG2 criteria and presented as Kaplan-Meier survival curves, as appropriate.
Time Frame	Up to 24 weeks

Outcome Measure Data

Analysis Population Description

Only 4 patients was accrued to this trial. No data analysis was performed.

Arm/Group Title	Treatment (Orteronel)
Arm/Group Description	Patients receive orteronel 300 mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. orteronel: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

4. Secondary Outcome

Title	Absolute Change in PSA
Description	Values will be tabulated as outlined in the PCWG2 criteria and presented as Kaplan-Meier survival curves, as appropriate.
Time Frame	Baseline to 24 weeks

Outcome Measure Data

Analysis Population Description

Only 4 patients was accrued to this trial. No data analysis was performed.

Arm/Group Title	Treatment (Orteronel)
Arm/Group Description	Patients receive orteronel 300 mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. orteronel: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

5. Secondary Outcome

Title	Overall Response Rate Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and PCWG2 Criteria
Description	Response will be tabulated descriptively with 95% confidence intervals (CIs) and Kaplan-Meier survival curves, as appropriate.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Only 4 patients was accrued to this trial. No data analysis was performed.

Arm/Group Title	Treatment (Orteronel)
Arm/Group Description	Patients receive orteronel 300 mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. orteronel: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

6. Secondary Outcome

Title	Duration of Response Using RECIST Version 1.1 and PCWG2 Criteria
Description	Response will be tabulated descriptively with 95% CIs and Kaplan-Meier survival curves, as appropriate.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Only 4 patients was accrued to this trial. No data analysis was performed.

Arm/Group Title	Treatment (Orteronel)
Arm/Group Description	Patients receive orteronel 300 mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. orteronel: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	0

7. Secondary Outcome

Title	Number of Participants With Grade 3 or Higher Toxicity
Description	Summary of grade 3 (per Common Terminology Criteria for Adverse Events (CTCAE v4.0) or higher toxicities which generally is described as a severe reaction or symptom.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Tracked during treatment period until 30 days after last dose of study drug.

Arm/Group Title	Treatment (Orteronel)
Arm/Group Description	Patients receive orteronel 300 mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. orteronel: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	4
Count of Participants [Participants]	1 25%

Adverse Events

Time Frame	Days 1, 8, 15, 21 of each cycle and treatment end (30 days after last dose or start of new treatment).
Arm/Group Title	Treatment (Orteronel)
Arm/Group Description	Patients receive orteronel 300 mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. orteronel: Given PO laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (Orteronel)
	Affected / at Risk (%)	# Events
Total	0/4 (0%)
Serious Adverse Events
	Treatment (Orteronel)
	Affected / at Risk (%)	# Events
Total	1/4 (25%)
Blood and lymphatic system disorders
Anemia	1/4 (25%)	1
Gastrointestinal disorders
Abdominal Pain	1/4 (25%)	1
Investigations
Platelet count decreased	1/4 (25%)	1
Vascular disorders
Hypertension	1/4 (25%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Orteronel)
	Affected / at Risk (%)	# Events
Total	3/4 (75%)
Blood and lymphatic system disorders
Anemia	1/4 (25%)	2
Cardiac disorders
Chest pain - cardiac	1/4 (25%)	1
Endocrine disorders
Adrenal insufficiency	1/4 (25%)	1
Gastrointestinal disorders
Abodminal Pain	2/4 (50%)	2
Constipation	2/4 (50%)	4
Diarrhea	1/4 (25%)	2
Nausea	3/4 (75%)	3
Stomach pain	2/4 (50%)	2
Toothache	1/4 (25%)	1
Vomiting	2/4 (50%)	2
General disorders
Fatigue	3/4 (75%)	4
Fever	2/4 (50%)	2
Pain	1/4 (25%)	1
Infections and infestations
Tooth infection	1/4 (25%)	1
Injury, poisoning and procedural complications
Bruising	1/4 (25%)	1
Investigations
Activated partial thromboplastin time prolonged	1/4 (25%)	1
Alkaline phosphatase increased	1/4 (25%)	1
Aspartate Aminotransferase increased	2/4 (50%)	2
Creatinine increased	1/4 (25%)	1
Electrocardiogram QT corrected interval prolonged	1/4 (25%)	1
Neutrophil count decreased	1/4 (25%)	1
Platelet count decreased	1/4 (25%)	2
White blood cell decreased	1/4 (25%)	1
Metabolism and nutrition disorders
Anorexia	3/4 (75%)	3
Hyperglycemia	2/4 (50%)	2
Hyperkalemia	1/4 (25%)	1
Hypocalcemia	1/4 (25%)	2
Hypokalemia	1/4 (25%)	1
Hyponatremia	1/4 (25%)	1
Hypophosphatemia	1/4 (25%)	1
Musculoskeletal and connective tissue disorders
Back pain	2/4 (50%)	2
Bone pain	1/4 (25%)	2
Generalized muscle weakness	1/4 (25%)	1
Pain in extremity	1/4 (25%)	2
Psychiatric disorders
Insomnia	1/4 (25%)	1
Libido decreased	2/4 (50%)	3
Renal and urinary disorders
Hematuria	1/4 (25%)	1
Urinary frequency	1/4 (25%)	2
Respiratory, thoracic and mediastinal disorders
Cough	3/4 (75%)	4
Dyspnea	1/4 (25%)	1
Nasal congestion	1/4 (25%)	1
Productive cough	1/4 (25%)	1
Vascular disorders
Hypertension	1/4 (25%)	1

Limitations/Caveats

The trial was terminated early due to the discontinuation of the development program for the study drug, TAK-700 (orteronel) for prostate cancer.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.