Phase Ib/II Study Evaluating Orteronel (Without Prednisone) Combined With Itraconazole In Men With Castration-Resistant Prostate Cancer (CRPC)
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Prostate Cancer, Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 5/5/2014 |
| Start Date: | June 2014 |
| End Date: | July 2016 |
| Contact: | Emmanuel Antonarakis, MD |
| Email: | eantona1@jhmi.edu |
| Phone: | 443-287-0553 |
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.
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.
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.
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.
Inclusion Criteria:
- > 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.
Exclusion Criteria:
- 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
- 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
We found this trial at
3
sites
Johns Hopkins University The Johns Hopkins University opened in 1876, with the inauguration of its...
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Barbara Ann Karmanos Cancer Institute Karmanos is based in southeast Michigan, in midtown Detroit, and...
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Sibley Memorial Hospital Sibley Memorial Hospital, in Northwest Washington, D.C., has a distinguished history of...
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