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AzTrials

Esophagus AdenocarcinomaPhase 2NCT04018872

Evaluating the Effect of Itraconazole on Pathologic Complete Response Rates in Esophageal Cancer

A Phase 2 study testing Itraconazole in people with Esophagus Adenocarcinoma and Esophagus Squamous Cell Carcinoma, run by Dallas VA Medical Center at 1 site in United States.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

Esophageal cancer, which has a low 5-year overall survival rate for all stages (<20%) , is increasing in incidence. Previous studies have shown that the Hedgehog (Hh) and AKT signaling pathways are activated in a significant proportion of esophageal cancers. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Itraconazole
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
78 participants
Where
1 siteUnited States
Study dates
24 Jun 2019to 29 Sep 2026
Phase
Phase 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
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients diagnosed with localized (locoregional) esophageal cancer
  • Patients diagnosed with localized (locoregional) gastroesophageal junction cancer

Who cannot join

  • Patients unwilling or unable to provide informed consent
  • Patients with QTc>450ms
  • Patients with a history of symptomatic congestive heart failure
  • Patients with LFT's>3xULN
  • Patients who are pregnant
  • Patients with a known allergy to itraconazole

Trial locations and contacts

1 site in 1 country.

David Wang, MD, PhD contact

214-857-0737

davidh.wang@va.gov

Thai Pham, MD contact

214-857-1800

thai.pham2@va.gov

United States1 site, 1 recruiting

  • Dallas VA Medical Center

    Dallas, Texas, 75216

    Jessica Vallejo, BSA

    214-857-4237, jessica.vallejo@va.gov

    Recruiting

Other trials in United States

About this study

Official title: A Phase II Trial Evaluating the Effectiveness of Itraconazole in Improving Pathologic Complete Response Rates in Patients With Esophageal Cancer Through Inhibition of the Hedgehog and AKT Signaling Pathways

Esophageal cancer, which has a low 5-year overall survival rate for all stages (<20%) , is increasing in incidence. Previous studies have shown that the Hedgehog (Hh) and AKT signaling pathways are activated in a significant proportion of esophageal cancers. Itraconazole, a widely used anti-fungal medication, has been shown to inhibit various pathways involved in esophageal cancer tumorigenesis including Hh and AKT. In this phase II clinical trial, the investigators aim to evaluate the effect of itraconazole as a neoadjuvant therapy following standard of care chemoradiation in the treatment of locoregional esophageal and gastroesophageal junction carcinomas.

Read the detailed description

Esophageal cancer has a high incidence rate in the United States, and novel approaches to its treatment are being studied. Itraconazole, an antifungal agent, has been shown to inhibit the Hedgehog (Hh) and AKT signaling pathways, which are upregulated in esophageal cancer and promote tumor cell growth. This study will evaluate whether the use of itraconazole leads to increased rates of pathological complete response (pathCR) by at least 15% from the historical pathCR rate of 25% in patients with esophageal cancer or gastroesophageal junction (GEJ) adenocarcinoma. The investigators will enroll approximately 78 patients with esophageal cancer or GEJ adenocarcinoma who will then undergo standard of care staging work-up with a PET/CT and endoscopic ultrasound (EUS). In a subset of patients, biopsies will be obtained to assess the status of the Hh and AKT signaling pathways by PCR, Western blot, and immunohistochemistry in the primary tumor before treatment. If no distant metastases are found, all patients will undergo 5-6 weeks of standard of care neoadjuvant chemoradiation. Following this, all patients will be given itraconazole 300 mg twice daily for 6-8 weeks. Adverse effects to itraconazole will be monitored in oncology clinic. If standard restaging PET/CT following neoadjuvant chemoradiation does not reveal new metastases, the patient will undergo an esophagectomy. Samples from normal esophageal tissue will be analyzed for presence of itraconazole and its metabolites to determine if the patients were taking the study drug. Tumor tissue will be evaluated for status of Hh pathway activation, AKT and VEGFR2 phosphorylation, Ki67 immunostaining, and other molecular pathways with comparisons made to pre-treatment biopsies if available. The final pathology report will indicate whether the patient has achieved pathCR. Because the Hh signaling pathway is a resistance pathway that can be upregulated in response to chemoradiation, the investigators believe that administering itraconazole following neoadjuvant chemoradiation will lead to a higher pathCR rate. This in turn should be able to improve treatment outcomes in patients with esophageal cancer and GEJ adenocarcinoma.

Being tested
Itraconazole
Keywords
itraconazole, esophageal neoplasms, esophagus, esophagogastric junction, adenocarcinoma, squamous cell carcinoma
Medical subject headings
Adenocarcinoma Of Esophagus, Esophageal Squamous Cell Carcinoma, Esophageal Neoplasms, Adenocarcinoma, Carcinoma, Squamous Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ItraconazoleDrug

    Oral administration of itraconazole twice daily from completion of neoadjuvant chemoradiation until esophagectomy.

Study groups in NCT04018872
Study groupRoleWhat they receive
ItraconazoleExperimentalItraconazole capsule 300mg twice daily for 6-8 weeks following chemoradation.
Receives: Drug: Itraconazole

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of pathological complete response with itraconazole

    Generally for esophageal cancer the pathological complete response rate at time of esophagectomy is 25%, and we have designed our study with the projected number of patients assuming we observe an improvement of 15% or more in this rate following treatment with itraconazole. This is the study's primary endpoint. By inhibiting the Hh signaling pathway with the use of itraconazole, we anticipate improved pathological complete response rates.

    Measured: 3-4 months

Secondary outcomes (3)

  1. Comparison of hedgehog biomarkers before and after intervention

    As part of clinical staging, patients will undergo endoscopic ultrasound (EUS) following a PET/CT that does not show metastases. During EUS, some patients will undergo eight research biopsies obtained with large forceps for research purposes at the level of the visualized esophageal mass or abnormality (3 for RNA isolation, 3 for protein isolation, and 2 for formalin fixation). Three research biopsies for RNA isolation will also be obtained from normal appearing esophagus, at least 5 cm away from any mass lesions. The research biopsies will be submitted to qPCR analysis for mRNA expression levels of SHH, IHH, PTCH, GLI1, GLI2, and GLI3 (Hedgehog pathway components). Comparisons will be made between mass biopsies and normal esophageal tissues. Following esophagectomy, tissues will be analyzed for the aforementioned hedgehog pathway markers to determine response to therapy.

    Measured: 3-4 months

  2. Comparison of phosphorylated VEGFR2 and AKT before and after intervention

    Tissue obtained prior to initiation of chemoradiation will be analyzed with Western blot to quantify presence of VEGFR2 and AKT. These markers will again be analyzed following esophagectomy to determine response to therapy.

    Measured: 3-4 months

  3. Levels of itraconazole and metabolites in esophageal tissue

    The concentration of itraconazole and hydroxy-itraconazole in normal esophageal tissue will be measured following esophagectomy to ensure that the drug has been taken consistently.

    Measured: 1 month.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Jul 2019
  2. Study start24 Jun 2019
  3. Primary completion24 Jun 2026 (estimated)
  4. Study completion29 Sep 2026 (estimated)

Resources

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 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
78 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04018872
Sponsor's protocol ID
19-017
Status last verified
Nov 2021
First submitted
10 Jul 2019
Last updated
4 Nov 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Kim DJ, Kim J, Spaunhurst K, Montoya J, Khodosh R, Chandra K, Fu T, Gilliam A, Molgo M, Beachy PA, Tang JY. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):745-51. doi: 10.1200/JCO.2013.49.9525. Epub 2014 Feb 3.

    PubMed 24493717

  • Antonarakis ES, Heath EI, Smith DC, Rathkopf D, Blackford AL, Danila DC, King S, Frost A, Ajiboye AS, Zhao M, Mendonca J, Kachhap SK, Rudek MA, Carducci MA. Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer. Oncologist. 2013;18(2):163-73. doi: 10.1634/theoncologist.2012-314. Epub 2013 Jan 22.

    PubMed 23340005

  • Nacev BA, Grassi P, Dell A, Haslam SM, Liu JO. The antifungal drug itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking, and signaling in endothelial cells. J Biol Chem. 2011 Dec 23;286(51):44045-44056. doi: 10.1074/jbc.M111.278754. Epub 2011 Oct 24.

    PubMed 22025615

  • Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, Reya T, Liu JO, Epstein EH, Stevens DA, Beachy PA. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010 Apr 13;17(4):388-99. doi: 10.1016/j.ccr.2010.02.027.

    PubMed 20385363

  • Chen MB, Liu YY, Xing ZY, Zhang ZQ, Jiang Q, Lu PH, Cao C. Itraconazole-Induced Inhibition on Human Esophageal Cancer Cell Growth Requires AMPK Activation. Mol Cancer Ther. 2018 Jun;17(6):1229-1239. doi: 10.1158/1535-7163.MCT-17-1094. Epub 2018 Mar 28.

    PubMed 29592879

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Itraconazole in people with Esophagus Adenocarcinoma and Esophagus Squamous Cell Carcinoma, run by Dallas VA Medical Center at 1 site 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 2 inclusion and 6 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: status not confirmed, as of the sponsor's last update on 4 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site 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 phase mean?

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?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact David Wang, MD, PhD (214-857-0737, davidh.wang@va.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of pathological complete response with itraconazole (time frame: 3-4 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04018872, which also lists 5 linked publications.

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 4 Nov 2021.

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