Phase Ib/II Study Evaluating Orteronel (Without Prednisone) Combined With Itraconazole In Men With Castration-Resistant Prostate Cancer (CRPC)

NCT02054793 | Withdrawn Phase 1 DMC

• 1 other identifier: Itraconazole/Orteronel
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 3

Brief 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. 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.

Conditions

Prostate Cancer; Castration-resistant Prostate Cancer

Keywords

metastatic disease; non-metastatic disease; prostate cancer; castration-resistant prostate cancer

Outcome Measures

Primary Outcomes (1)

• 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.

  12 months after study initiation

Secondary Outcomes (1)

• Grade and severity of adverse events

  up to 25 months

Interventions

Itraconazole DRUG

100 mg 200 mg 300 mg

Also known as: Sporanox

Orteronel DRUG

300 mg

Also known as: TAK 700

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \> 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Emmanuel Antonarakis, MD: lead
• Millennium Pharmaceuticals, Inc.: collaborator

Study Sites (3)

Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21231, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms; Neoplasm Metastasis

Interventions

Itraconazole; orteronel

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines

Study Officials

• EMMANUEL ANTONARAKIS, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: January 30, 2014
• First Posted: February 4, 2014
• Study Start: June 1, 2014
• Primary Completion: June 1, 2015
• Study Completion: July 1, 2016
• Last Updated: July 23, 2014

Record last verified: 2014-07

Locations

US (3)