A Phase II Trial to Evaluate the Effect of Itraconazole on Pathologic Complete Response Rates in Resectable Esophageal Cancer

NCT ID: NCT05563766

Last Updated: 2025-11-05

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 78 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-10-01
• Study Completion Date: 2029-06-15

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.

Detailed Description

Esophageal cancer has a high incidence rate in the United States, and novel approaches to improve its treatment are being studied. Itraconazole, an antifungal agent approved by the FDA in 1992, has been shown to inhibit the Hedgehog (Hh), AKT, and VEGFR2 signaling pathways which are upregulated in esophageal cancer and promote tumor growth. This study will evaluate whether the use of itraconazole leads to increased rates of pathologic complete response (pathCR) by at least 15% compared to propensity-score matched control patients with esophageal or gastroesophageal junction (GEJ) cancer. The investigators will enroll 78 patients with esophageal or GEJ cancer who will undergo standard of care staging workup with a PET/CT and endoscopic ultrasound (EUS). If no distant metastases are found, patients will receive 2 weeks of oral itraconazole before starting standard of care neoadjuvant chemoradiation. Upon completion of chemoradiation, patients will receive oral itraconazole for 6-8 weeks. Adverse effects to itraconazole will be monitored and drug levels will be obtained during clinic visits. If standard restaging PET/CT following neoadjuvant chemoradiation does not reveal new metastases, patients will undergo esophagectomy after consultation with their physician team. Samples from normal esophageal tissue will be analyzed for presence of itraconazole and its metabolite to determine if patients were compliant in taking study drug. Residual tumor tissue will be evaluated for status of the Hh, AKT, and VEGFR2 pathways with comparisons made to pre-treatment biopsies. The final pathology report will indicate whether the patient has achieved pathCR. Because Hh, AKT, and angiogenic signaling pathways can be upregulated in response to chemoradiation, the investigators believe that administering itraconazole around chemoradiation will lead to higher pathCR rates. This in turn should be able to improve treatment outcomes in patients with esophageal and GEJ cancer. Secondary endpoints include correlating drug levels and molecular pathway status to pathCR, determining a genomic profile that predicts treatment response, and evaluating ctDNA and exosomes as additional markers of treatment response.

Conditions

Esophageal Adenocarcinoma; Esophageal Squamous Cell Carcinoma; Gastroesophageal Junction Carcinoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Itraconazole

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

Group Type: EXPERIMENTAL

Itraconazole

Intervention Type: DRUG

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

Interventions

Itraconazole

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Durham VA Health Care System

FED

Sponsor Role: collaborator

VA Palo Alto Health Care System

FED

Sponsor Role: collaborator

Portland VA Medical Center

FED

Sponsor Role: collaborator

VA Puget Sound Health Care System

FED

Sponsor Role: collaborator

Michael E. DeBakey VA Medical Center

FED

Sponsor Role: collaborator

VA Boston Healthcare System

FED

Sponsor Role: collaborator

North Texas Veterans Healthcare System

FED

Sponsor Role: collaborator

VA Ann Arbor Healthcare System

FED

Sponsor Role: collaborator

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David H Wang, MD PhD

Role: PRINCIPAL_INVESTIGATOR

VA Ann Arbor Healthcare System, Ann Arbor, MI

Locations

VA Palo Alto Health Care System, Palo Alto, CA

Palo Alto, California, United States

Site Status: RECRUITING

VA Ann Arbor Healthcare System, Ann Arbor, MI

Ann Arbor, Michigan, United States

Site Status: RECRUITING

Durham VA Medical Center, Durham, NC

Durham, North Carolina, United States

Site Status: RECRUITING

VA Portland Health Care System, Portland, OR

Portland, Oregon, United States

Site Status: RECRUITING

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

Dallas, Texas, United States

Site Status: RECRUITING

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, United States

Site Status: RECRUITING

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

Seattle, Washington, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

David H Wang, MD PhD

Role: CONTACT

davidh.wang@va.gov

Facility Contacts

Albert Lin, MD

Role: primary

albert.lin6@va.gov

650-493-5000 ext. 69523

Laura A Randolph, BA

Role: primary

Laura.Randolph@va.gov

734-845-5091

Michael Kelley, MD

Role: primary

michael.kelley6@va.gov

919-286-0411 ext. 172199

Kenneth Bensch, MD

Role: primary

kenneth.bensch1@va.gov

503-220-8262 ext. 5594

Nicole Pore-Brown

Role: primary

Florine.Pore-Brown@va.gov

214-857-3291

Yvonne Sada, MD

Role: primary

yvonne.sada@va.gov

713-794-7454

Daniel Wu, MD

Role: primary

daniel.wu@va.gov

206-764-2182

References

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.

Reference Type: BACKGROUND

PMID: 34376577 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20385363 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 29592879 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31290765 (View on PubMed)

Other Identifiers

I01CX002349

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ONCB-016-21F

Identifier Type: -

Identifier Source: org_study_id