NCT05563766

Brief Summary

Esophageal cancer, which has a low 5-year overall survival rate (\<20%) is increasing in incidence. Previous studies have shown that Hedgehog, AKT, and angiogenic signaling pathways are activated in a significant number of esophageal cancers. Itraconazole, a widely used anti-fungal medication, effectively inhibits these pathways. In this multi-site phase II trial, the investigators will evaluate the effect of itraconazole as a neoadjuvant therapy added to standard of care chemoradiation and surgery in the the treatment of locoregional esophageal and gastroesophageal junction cancers.

Trial Health

77
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
78

participants targeted

Target at P50-P75 for phase_2

Timeline
38mo left

Started Oct 2024

Longer than P75 for phase_2

Geographic Reach
1 country

7 active sites

Status
recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress34%
Oct 2024Jun 2029

First Submitted

Initial submission to the registry

September 27, 2022

Completed
6 days until next milestone

First Posted

Study publicly available on registry

October 3, 2022

Completed
2 years until next milestone

Study Start

First participant enrolled

October 1, 2024

Completed
4.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

April 30, 2029

Expected
2 months until next milestone

Study Completion

Last participant's last visit for all outcomes

June 15, 2029

Last Updated

November 5, 2025

Status Verified

November 1, 2025

Enrollment Period

4.6 years

First QC Date

September 27, 2022

Last Update Submit

November 3, 2025

Conditions

Esophageal AdenocarcinomaEsophageal Squamous Cell CarcinomaGastroesophageal Junction Carcinoma

Keywords

ItraconazoleNeoadjuvant

Outcome Measures

Primary Outcomes (1)

  • Rate of pathological complete response with itraconazole

    Historically, the pathCR rate at time of esophagectomy is 25%. The investigators have powered our study to detect a 15% or more improvement in pathCR rate following treatment with itraconazole. By inhibiting pathways that mediate chemoradiation resistance, the investigators anticipate an improved pathCR rate.

    20 weeks

Secondary Outcomes (4)

  • Comparison of Hedgehog, AKT, and angiogenesis pathway status before and after intervention

    20 weeks

  • Correlation of peripheral blood and esophageal tissue levels of itraconazole and hydroxyitraconazole with pathologic response

    20 weeks

  • Develop a predictive genomic profile of treatment response

    20 weeks

  • Determine the utility of ctDNA and exosome characterization as a prognostic marker

    20 weeks

Study Arms (1)

Itraconazole

EXPERIMENTAL

Itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after completion of standard of care neoadjuvant chemoradiation

Drug: Itraconazole

Interventions

ItraconazoleDRUG

Itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after completion of standard of care neoadjuvant chemoradiation

Itraconazole

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Capable of giving informed consent
  • Pathologic diagnosis of esophageal cancer (ESCC or EAC) or GEJ cancer deemed resectable by a surgeon with a plan to undergo neoadjuvant chemoradiation and curative intent esophagectomy
  • World Health Organization (WHO)/ECOG performance status (PS) of 0-2 at enrollment
  • Adequate renal and liver function as judged by the treating physician

You may not qualify if:

  • Inability to provide Informed Consent
  • NYHA class III or IV CHF
  • LFT\>3X upper limit of normal
  • Drug allergy to itraconazole
  • Positive pregnancy test
  • Those with QTc\>450 ms will have QTc monitored during therapy by serial EKG to ensure QTc does not lengthen to what the treating clinician considers significant

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (7)

VA Palo Alto Health Care System, Palo Alto, CA

Palo Alto, California, 94304-1207, United States

RECRUITING

VA Ann Arbor Healthcare System, Ann Arbor, MI

Ann Arbor, Michigan, 48105-2303, United States

RECRUITING

Durham VA Medical Center, Durham, NC

Durham, North Carolina, 27705-3875, United States

RECRUITING

VA Portland Health Care System, Portland, OR

Portland, Oregon, 97207-2964, United States

RECRUITING

VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Dallas, Texas, 75216-7167, United States

RECRUITING

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, 77030-4211, United States

RECRUITING

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Seattle, Washington, 98108-1532, United States

RECRUITING

Related Publications (4)

  • Zhang W, Bhagwath AS, Ramzan Z, Williams TA, Subramaniyan I, Edpuganti V, Kallem RR, Dunbar KB, Ding P, Gong K, Geurkink SA, Beg MS, Kim J, Zhang Q, Habib AA, Choi SH, Lapsiwala R, Bhagwath G, Dowell JE, Melton SD, Jie C, Putnam WC, Pham TH, Wang DH. Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway. Mol Cancer Ther. 2021 Oct;20(10):1904-1915. doi: 10.1158/1535-7163.MCT-20-0638. Epub 2021 Aug 10.

    PMID: 34376577BACKGROUND

  • 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.

    PMID: 20385363BACKGROUND

  • 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.

    PMID: 29592879BACKGROUND

  • Kelly RJ, Ansari AM, Miyashita T, Zahurak M, Lay F, Ahmed AK, Born LJ, Pezhouh MK, Salimian KJ, Ng C, Matsangos AE, Stricker-Krongrad AH, Mukaisho KI, Marti GP, Chung CH, Canto MI, Rudek MA, Meltzer SJ, Harmon JW. Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett's Esophagus to Invasive Esophageal Adenocarcinoma. Ann Surg. 2021 Jun 1;273(6):e206-e213. doi: 10.1097/SLA.0000000000003455.

    PMID: 31290765BACKGROUND

MeSH Terms

Conditions

Adenocarcinoma Of EsophagusEsophageal Squamous Cell Carcinoma

Interventions

Itraconazole

Condition Hierarchy (Ancestors)

Carcinoma, Squamous CellCarcinomaNeoplasms, Glandular and EpithelialNeoplasms by Histologic TypeNeoplasmsNeoplasms, Squamous CellEsophageal NeoplasmsGastrointestinal NeoplasmsDigestive System NeoplasmsNeoplasms by SiteHead and Neck NeoplasmsDigestive System DiseasesEsophageal DiseasesGastrointestinal Diseases

Intervention Hierarchy (Ancestors)

TriazolesAzolesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsPiperazines

Study Officials

  • David H Wang, MD PhD

    VA Ann Arbor Healthcare System, Ann Arbor, MI

    PRINCIPAL INVESTIGATOR

Central Study Contacts

David H Wang, MD PhD

CONTACT

davidh.wang@va.gov

Study Design

Study Type
interventional
Phase
phase 2
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Model Details: Single arm, patients will receive itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after standard of care neoadjuvant chemoradiation.
Sponsor Type
FED
Responsible Party
SPONSOR

Study Record Dates

First Submitted

September 27, 2022

First Posted

October 3, 2022

Study Start

October 1, 2024

Primary Completion (Estimated)

April 30, 2029

Study Completion (Estimated)

June 15, 2029

Last Updated

November 5, 2025

Record last verified: 2025-11

Data Sharing

IPD Sharing
Will not share

Locations

US(7)