Phase Ib/II Study Evaluating Orteronel (Without Prednisone) Combined With Itraconazole In Men With Castration-Resistant Prostate Cancer (CRPC)
|ClinicalTrials.gov Identifier: NCT02054793|
Recruitment Status : Withdrawn (This study was never able to open due to lack of funding from the pharmaceutical company.)
First Posted : February 4, 2014
Last Update Posted : July 23, 2014
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.
|Condition or disease||Intervention/treatment||Phase|
|Prostate Cancer Castration-resistant Prostate Cancer||Drug: Itraconazole Drug: Orteronel||Phase 1 Phase 2|
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 Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||0 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase Ib/II Study Evaluating Orteronel (Without Prednisone) Combined With Itraconazole In Men With Castration-Resistant Prostate Cancer (CRPC)|
|Study Start Date :||June 2014|
|Estimated Primary Completion Date :||June 2015|
|Estimated Study Completion Date :||July 2016|
- Drug: Itraconazole
100 mg 200 mg 300 mgOther Name: Sporanox
- Drug: Orteronel
300 mgOther Name: TAK 700
- 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.
- Grade and severity of adverse events [ Time Frame: up to 25 months ]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
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02054793
|United States, District of Columbia|
|Sibley Memorial Hospital|
|Washington, District of Columbia, United States, 20016|
|United States, Maryland|
|Johns Hopkins University|
|Baltimore, Maryland, United States, 21231|
|United States, Michigan|
|Karmanos Cancer Institute|
|Detroit, Michigan, United States|
|Principal Investigator:||EMMANUEL ANTONARAKIS, MD||Johns Hopkins University|