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

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Project Summary
Esophageal cancer has a higher incidence rate in US veterans than the general population, and
its prognosis is generally poor with a five-year overall survival rate of less than 20%. While
most clinical trials focus on patients with metastatic esophageal cancer, novel therapies added
to curative intent chemoradiation and surgery in patients with localized esophageal cancer have
the greatest potential to improve overall survival rates. Patients who achieve a pathologic
complete response on esophagectomy after chemoradiation have a five-year overall survival
rate of 50%. Thus, a worthy goal is to increase the number of patients who achieve a
pathologic complete response. Treatment of esophageal cancer cells and xenografts with
itraconazole, a commonly used antifungal medication, inhibited cellular proliferation and AKT
and Hedgehog signaling, two pathways suspected of mediating chemoradiation resistance. In a
completed phase 0 trial, we found that a two-week course of oral itraconazole given before
chemoradiation was safely tolerated by patients and successfully inhibited AKT and Hedgehog
signaling in tumors. We now propose a single-arm phase II trial in which 78 patients will receive
oral itraconazole for an eight-week course between standard of care chemoradiation and
esophagectomy. The rationale for administering itraconazole during this period is several fold:
1) if AKT and Hedgehog signaling are upregulated by chemoradiation in esophageal cancer,
then more cancer cells would be susceptible to itraconazole after chemoradiation; 2) we can
administer itraconazole for a longer duration than in our phase 0 trial; and 3) patients are not
actively being treated during the proposed administration time period which provides a window
of opportunity. Our primary endpoint will be the pathologic complete response rate as assessed
by pathology review at the time of esophagectomy in these 78 patients as compared to 156
contemporary propensity score-matched controls. Secondary endpoints include 1) determining
if plasma and esophageal levels of itraconazole and hydroxyitraconazole in all patients and
molecular pathway status in residual tumors correlate with treatment response and 2)
determining if circulating tumor DNA levels, as measured by Natera's Signatera test, correlate
with treatment response. As part of the Signatera test, we will also obtain germline and somatic
tumor whole exome sequencing data from each patient. Specific Aim 1 will test the hypothesis
that itraconazole will increase the pathologic complete response rate by at least 15% compared
to controls. Specific Aim 2 will determine if treatment response correlates with drug and
metabolite levels in plasma and esophageal tissue and AKT and Hedgehog pathway status and
microvessel density (VEGFR2 pathway status) in residual tumors. Specific Aim 3 will utilize
whole exome sequencing of untreated tumors to develop a comprehensive genomic profile that
predicts treatment response (pre...

## Key facts

- **NIH application ID:** 11289169
- **Project number:** 7I01CX002349-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** DAVID H WANG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 7
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11289169

## Citation

> US National Institutes of Health, RePORTER application 11289169, A Phase II Trial to Evaluate the Effect of Itraconazole on Pathologic Complete Response Rates in Resectable Esophageal Cancer (7I01CX002349-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11289169. Licensed CC0.

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