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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Esophageal Adenocarcinoma; Esophageal Squamous Cell Carcinoma; Gastroesophageal Junction Carcinoma
• Intervention / Treatment: Drug: Itraconazole

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.

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: David H Wang, MD PhD; Phone Number: (214) 857-0737; Email: davidh.wang@va.gov
• Study Contact Backup: Name: Jonathan Dowell, MD; Phone Number: (214) 857-0737; Email: Jonathan.Dowell@va.gov

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304-1290
      • VA Palo Alto Health Care System, Palo Alto, CA
      • Contact: Albert Lin, MD; Phone Number: 69523 650-493-5000; Email: albert.lin6@va.gov
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Durham VA Medical Center, Durham, NC
      • Contact: Michael Kelley, MD; Phone Number: 172199 919-286-0411; Email: michael.kelley6@va.gov
  • Oregon
    • Portland, Oregon, United States, 97239
      • VA Portland Health Care System, Portland, OR
      • Contact: Kenneth Bensch, MD; Phone Number: 5594 503-220-8262; Email: kenneth.bensch1@va.gov
  • Texas
    • Dallas, Texas, United States, 75216-7167
      • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
      • Principal Investigator: David H Wang, MD PhD
      • Contact: Amy Atwell; Phone Number: 214-857-2234; Email: amy.atwell@va.gov
      • Contact: Cedric Pereznegron; Phone Number: (214) 857-0826; Email: cedric.pereznegron@va.gov
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center, Houston, TX
      • Contact: Yvonne Sada, MD; Phone Number: 713-794-7454; Email: yvonne.sada@va.gov
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System Seattle Division, Seattle, WA
      • Contact: Daniel Wu, MD; Phone Number: 206-764-2182; Email: daniel.wu@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Itraconazole; Itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after completion of standard of care neoadjuvant chemoradiation	Drug: Itraconazole; Itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after completion of standard of care neoadjuvant chemoradiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of Hedgehog, AKT, and angiogenesis pathway status before and after intervention	After completion of pathologic staging of any residual tumor at esophagectomy, FFPE sections will be analyzed for expression of SHH, GLI, HER2, phospho-S6, and CD34 by IHC or ISH and compared to untreated biopsies.	20 weeks
Correlation of peripheral blood and esophageal tissue levels of itraconazole and hydroxyitraconazole with pathologic response	Peripheral blood will be obtained during a standard of care clinic visit and squamous esophageal tissue collected at esophagectomy. These levels will be correlated with pathologic response.	20 weeks
Develop a predictive genomic profile of treatment response	Whole exome sequencing will be obtained on pre-treatment tumors from all enrolled patients. VA Boston HCS will use multiple algorithms to develop a genomic profile that predicts treatment response.	20 weeks
Determine the utility of ctDNA and exosome characterization as a prognostic marker	CtDNA will be obtained at 4 timepoints and exosomes will be collected at 3 timepoints during treatment. Changes in ctDNA quantitation and exosome characteristics will be correlated with pathologic treatment response.	20 weeks

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: VA Palo Alto Health Care System; VA Puget Sound Health Care System; Michael E. DeBakey VA Medical Center; VA Boston Healthcare System; Durham VA Health Care System; Portland VA Medical Center
• Investigators: Principal Investigator: David H Wang, MD PhD, VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): June 15, 2029

Study Registration Dates

• First Submitted: September 27, 2022
• First Submitted That Met QC Criteria: September 28, 2022
• First Posted (Actual): October 3, 2022

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Neoadjuvant; Itraconazole
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Disease Progression; Carcinoma; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Pathologic Complete Response; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole
• Other Study ID Numbers: ONCB-016-21F; I01CX002349 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes