Prostate CancerPhase 1/2NCT02054793
Phase Ib/II Study Evaluating Orteronel (Without Prednisone) Combined With Itraconazole In Men With Castration-Resistant Prostate Cancer (CRPC)
A Phase 1/2 study testing Itraconazole and Orteronel in people with Prostate Cancer and Castration-resistant Prostate Cancer, run by Emmanuel Antonarakis, MD at 3 sites in United States.
Trial summary
This research is being done to test the safety and anti-cancer activity of the combination of an investigational drug called orteronel, with a drug called itraconazole in the treatment of castration-resistant prostate cancer. Read more about this study
- Who is it for?
- Ages 18 years and older, men only
- Conditions the study is for
- Prostate Cancer, Castration-resistant Prostate Cancer
- What is being tested?
- Itraconazole and Orteronel
- How many people
- 0 participants
- Where
- 3 sitesUnited States
- Study dates
- Jun 2014to Jul 2016
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- > 18 years of age
- must provide written consent
- must agree to use contraception
- has a diagnosis of castrate resistant prostate cancer
- normal clinical lab values ALT and AST must be ≤ 2.5 x the upper limit of normal (ULN). Total bilirubin must be ≤ 1.5 x ULN. Estimated creatinine clearance using the Cockcroft-Gault formula must be > 40 mL/minute Absolute neutrophil count (ANC) must be ≥ 1500/uL Platelet count must be ≥ 100,000/uL
- has stable medical conditions (including absence of acute exacerbations of chronic illnesses, serious infections or major surgery within 4 weeks before first dose of drug
- castrate level of testosterone (< 50ng/dL)
- screening calculated ejection fraction of > 50% by ECHO.
Who cannot join
- received prior therapy with orteronel, ketoconazole, aminoglutethimide, or abiraterone. Prior enzalutamide treatment is permitted.
- prior use of docetaxel for CRPC
- symptomatic metastatic disease with signs of rapid progression per investigator's clinical judgment or hepatic metastases
- currently receiving corticosteroids
- concurrent use of acid-lowering drugs (histamine antagonists, proton pump inhibitors)
- known hypersensitivity to compounds related to orteronel, orteronel excipients, itraconazole or related compounds including other azole antifungals
Show all 15Show fewer
- concurrent administration of other drugs that significantly interact with CYP450 3A4 isoenzyme
- known brain metastases
- treatment with any investigational products within one month before the first dose of study drug
- diagnosis of or treatment for another systemic malignancy within 2 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease
- history of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of Grade >2 (NCI CTCAE version 4.0, effective dates 14 June 2010), thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (e.g. pericardial effusion, restrictive
- has New York Heart Association (NYHA) Class III or IV heart failure
- uncontrolled hypertension despite appropriate medical therapy (systolic blood pressure >160 mm Hg or diastolic blood pressure >90 mmHg) at 2 separate measurements no more than 60 minutes apart during the Screening visit).
- has known gastrointestinal (GI) disease or GI procedure that could interfere with the GI absorption or tolerance of orteronel, including difficulty swallowing tablets
- likely unable to comply with the protocol or cooperate fully with the investigator and site personnel
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Johns Hopkins University
Baltimore, Maryland, 21231
Karmanos Cancer Institute
Detroit, Michigan
Sibley Memorial Hospital
Washington D.C., District of Columbia, 20016
About this study
This research is being done to test the safety and anti-cancer activity of the combination of an investigational drug called orteronel, with a drug called itraconazole in the treatment of castration-resistant prostate cancer.
Orteronel is an investigational drug known as a 17,20-lyase enzyme inhibitor, meaning that it blocks the formation of male sex hormones.
Read more
Itraconazole is approved by the Food and Drug Administration (FDA) for the treatment of various fungal infections such as fingernail/toenail infections and other more serious fungal infections. While it has shown evidence of activity against prostate cancer in prior studies, it is not approved for use in cancer. The FDA is allowing the use of orteronel and itraconazole in this research study. In addition to its antifungal properties, itraconazole was discovered to function to block angiogenesis (blood vessel formation to tumors) to block a cellular pathway thought to be important in prostate cancer known as the Hedgehog pathway.
Investigators hypothesize that blocking male sex hormone production with orteronel will increase reliance on the Hedgehog pathway in prostate cancer cells which can then be blocked with itraconazole and that the combination of these two drugs will be more effective than either alone.
Read the detailed description
Hedgehog (Hh) pathway signaling may be important in prostate cancer progression and this pathway is upregulated in the castration-resistant state. More potent (maximal) castration achievable by CYP17 inhibition, using orteronel, may further upregulate Hh pathway activation. Itraconazole administered at high doses (600 mg/day) may function as a modest Hh inhibitor. In a pilot phase II trial, investigators have shown that single-agent high-dose itraconazole produced PSA reductions in 29% of men with metastatic castration-resistant prostate cancer (CRPC), reduced circulating tumor cell counts in 62% of patients with unfavorable baseline counts, and prolonged progression-free survival compared to historical data. Moreover, clinical responses to itraconazole appeared to correlate with Hh pathway suppression, as measured by GLI1 mRNA analysis from serial skin biopsies.
Investigators propose to evaluate the potent CYP17/lyase inhibitor, orteronel, in combination with itraconazole at escalating dose levels (100 mg BID, 200 mg BID, 300 mg BID) in men with non-metastatic or metastatic CRPC by conducting an open-label phase Ib/II trial. Importantly, unlike the related compound, ketoconazole, itraconazole very rarely results in adrenal suppression. Side effects previously seen at the highest dose of itraconazole (600 mg/day) were mild and included nausea, rash, diarrhea, vomiting, hypokalemia, edema, headache, hypertension, fever, pruritis, and abnormal liver function tests. Of note, orteronel will be given without concurrent prednisone in this trial. This is because the combination of itraconazole and corticosteroids can lead to Cushing's syndrome (hypercortisolism) by impairing corticosteroid metabolism through CYP3A4.
Therefore, this study provides an opportunity to evaluate a steroid-free orteronel combination regimen. If this combination is safe and tolerable, subsequent studies would aim to compare the clinical efficacy of orteronel-itraconazole versus orteronel alone using a randomized phase II trial design.
- Being tested
- Itraconazole, Orteronel
- Keywords
- metastatic disease, non-metastatic disease, prostate cancer, castration-resistant prostate cancer
- Medical subject headings
- Prostatic Neoplasms, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ItraconazoleDrug
Also called Sporanox
100 mg 200 mg 300 mg
OrteronelDrug
Also called TAK 700
300 mg
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose
This is a dose escalation phase I trial where 3 subjects will be enrolled at each dose level. If no dose limiting toxicities (DLTs) are seen at a dose level, the study moves to the next dose level. If 1 DLT is seen, 3 additional subjects must be enrolled at the current dose level. If 2-3 DLTs are seen, we will stop accrual to that particular dose level, and the previous dose level becomes the maximum tolerated dose.
Measured: 12 months after study initiation
Secondary outcomes (1)
Grade and severity of adverse events
To determine the safety and tolerability of the combination regimen: orteronel + itraconazole. The grade and severity of adverse events will be assessed using CTCAE v4.0
Measured: up to 25 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Feb 2014 (estimated)
- Study startJun 2014
- Primary completionJun 2015 (estimated)
- Study completionJul 2016 (estimated)
Why it stopped: This study was never able to open due to lack of funding from the pharmaceutical company.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Prostate CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Emmanuel Antonarakis, MD
- Sponsor type
- University, hospital or other
- Collaborators
- Millennium Pharmaceuticals, Inc.
- Responsible party
- Sponsor-investigator, Emmanuel Antonarakis, MD, Johns Hopkins University
- Investigators
- EMMANUEL ANTONARAKIS, MD, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02054793
- Sponsor's protocol ID
- Itraconazole/Orteronel
- Status last verified
- Jul 2014
- First submitted
- 30 Jan 2014
- Last updated
- 23 Jul 2014
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 23 Jul 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase Ib/II Study Evaluating Orteronel (Without Prednisone) Combined With Itraconazole In Men With Castration-Resistant Prostate Cancer (CRPC)
- ClinicalTrials.gov ID
- NCT02054793
- Acronym / sponsor ID
- Itraconazole/Orteronel
- Keywords
- metastatic disease, non-metastatic disease, prostate cancer, castration-resistant prostate cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: This study was never able to open due to lack of funding from the pharmaceutical company.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Emmanuel Antonarakis, MDUniversity, hospital or other
- Collaborators
- Millennium Pharmaceuticals, Inc.
- Study start
- Jun 2014
- Primary completion
- Jun 2015 (estimated)
- Study completion
- Jul 2016 (estimated)
- First posted
- 4 Feb 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This research is being done to test the safety and anti-cancer activity of the combination of an investigational drug called orteronel, with a drug called itraconazole in the treatment of castration-resistant prostate cancer.
Orteronel is an investigational drug known as a 17,20-lyase enzyme inhibitor, meaning that it blocks the formation of male sex hormones.
Itraconazole is approved by the Food and Drug Administration (FDA) for the treatment of various fungal infections such as fingernail/toenail infections and other more serious fungal infections. While it has shown evidence of activity against prostate cancer in prior studies, it is not approved for use in cancer. The FDA is allowing the use of orteronel and itraconazole in this research study. In addition to its antifungal properties, itraconazole was discovered to function to block angiogenesis (blood vessel formation to tumors) to block a cellular pathway thought to be important in prostate cancer known as the Hedgehog pathway.
Investigators hypothesize that blocking male sex hormone production with orteronel will increase reliance on the Hedgehog pathway in prostate cancer cells which can then be blocked with itraconazole and that the combination of these two drugs will be more effective than either alone.
Detailed description
Hedgehog (Hh) pathway signaling may be important in prostate cancer progression and this pathway is upregulated in the castration-resistant state. More potent (maximal) castration achievable by CYP17 inhibition, using orteronel, may further upregulate Hh pathway activation. Itraconazole administered at high doses (600 mg/day) may function as a modest Hh inhibitor. In a pilot phase II trial, investigators have shown that single-agent high-dose itraconazole produced PSA reductions in 29% of men with metastatic castration-resistant prostate cancer (CRPC), reduced circulating tumor cell counts in 62% of patients with unfavorable baseline counts, and prolonged progression-free survival compared to historical data. Moreover, clinical responses to itraconazole appeared to correlate with Hh pathway suppression, as measured by GLI1 mRNA analysis from serial skin biopsies.
Investigators propose to evaluate the potent CYP17/lyase inhibitor, orteronel, in combination with itraconazole at escalating dose levels (100 mg BID, 200 mg BID, 300 mg BID) in men with non-metastatic or metastatic CRPC by conducting an open-label phase Ib/II trial. Importantly, unlike the related compound, ketoconazole, itraconazole very rarely results in adrenal suppression. Side effects previously seen at the highest dose of itraconazole (600 mg/day) were mild and included nausea, rash, diarrhea, vomiting, hypokalemia, edema, headache, hypertension, fever, pruritis, and abnormal liver function tests. Of note, orteronel will be given without concurrent prednisone in this trial. This is because the combination of itraconazole and corticosteroids can lead to Cushing's syndrome (hypercortisolism) by impairing corticosteroid metabolism through CYP3A4.
Therefore, this study provides an opportunity to evaluate a steroid-free orteronel combination regimen. If this combination is safe and tolerable, subsequent studies would aim to compare the clinical efficacy of orteronel-itraconazole versus orteronel alone using a randomized phase II trial design.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 18 years and older
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- > 18 years of age
- must provide written consent
- must agree to use contraception
- has a diagnosis of castrate resistant prostate cancer
- normal clinical lab values ALT and AST must be ≤ 2.5 x the upper limit of normal (ULN). Total bilirubin must be ≤ 1.5 x ULN. Estimated creatinine clearance using the Cockcroft-Gault formula must be > 40 mL/minute Absolute neutrophil count (ANC) must be ≥ 1500/uL Platelet count must be ≥ 100,000/uL
Key exclusion criteria (15 listed)
- received prior therapy with orteronel, ketoconazole, aminoglutethimide, or abiraterone. Prior enzalutamide treatment is permitted.
- prior use of docetaxel for CRPC
- symptomatic metastatic disease with signs of rapid progression per investigator's clinical judgment or hepatic metastases
- currently receiving corticosteroids
- concurrent use of acid-lowering drugs (histamine antagonists, proton pump inhibitors)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ItraconazoleAlso: Sporanox100 mg 200 mg 300 mg | Drug | – |
| OrteronelAlso: TAK 700300 mg | Drug | – |
Primary outcome
Maximum Tolerated Dose
Time frame: 12 months after study initiation
This is a dose escalation phase I trial where 3 subjects will be enrolled at each dose level. If no dose limiting toxicities (DLTs) are seen at a dose level, the study moves to the next dose level. If 1 DLT is seen, 3 additional subjects must be enrolled at the current dose level. If 2-3 DLTs are seen, we will stop accrual to that particular dose level, and the previous dose level becomes the maximum tolerated dose.
1 secondary outcome
Grade and severity of adverse events
Time frame: up to 25 months
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jul 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
EMMANUEL ANTONARAKIS, MD principal investigator
Johns Hopkins University
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Itraconazole and Orteronel in people with Prostate Cancer and Castration-resistant Prostate Cancer, run by Emmanuel Antonarakis, MD at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 23 Jul 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (time frame: 12 months after study initiation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2014; AzTrials last refreshed its copy on 30 Oct 2026.