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Principal Investigator: DAVID H WANG
Organization: VA NORTH TEXAS HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
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 (precision medicine) and determine if treatment response and
recurrence-free survival correlate with circulating tumor DNA levels in the blood as measured by
Signatera.
Terms: <1-Phosphatidylinositol 3-Kinase><AKT><AKT inhibition><Adverse Experience><Adverse event><Affect><Akt protein><Angiogenesis Inhibition><Angiogenic Inhibition><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Benign and Malignant Esophageal Neoplasms><Biopsy><Blood><Blood Plasma><Blood Reticuloendothelial System><Cancer Drug><Cell Communication and Signaling><Cell Cycle Arrest><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cellular Proliferation><Clinical Trials><Data><Detectable Residual Disease><Disease><Disorder><Drugs><ERBB2><ERBB2 gene><Erinaceidae><Esophageal Cancer><Esophageal Neoplasia><Esophageal Neoplasms><Esophageal Tissue><Esophageal Tumor><Esophagectomy><Esophagus><Esophagus Cancer><Esophagus Neoplasm><Esophagus Tumor><Exposure to><FLK1><G1/S Transition><General Population><General Public><Generalized Growth><Genomics><Germ Lines><Goals><Growth><HER -2><HER-2><HER-2 inhibition><HER2><HER2 Genes><HER2 inhibition><HER2/neu><Hedgehog (Hh) signal transduction pathway><Hedgehogs><Heterograft><Heterologous Transplantation><In complete remission><Incidence><Induction Therapy><Institution><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Itraconazole><KDR gene><Malignant Cell><Malignant Esophageal Neoplasm><Malignant Esophageal Tumor><Malignant Tumor of the Esophagus><Malignant neoplasm of esophagus><Measurement><Measures><Mediating><Medication><Minimal Residual Disease><Molecular><Monitor><Morbidity><Morbidity - disease rate><NEOADJ><NEU Oncogene><NEU protein><NOD/SCID mouse><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplastic Disease Chemotherapeutic Agents><Oncogene ErbB2><Oncogenic><Operative Procedures><Operative Surgical Procedures><Oral><Outcome><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><Pathologic><Pathology><Pathway interactions><Patients><Pharmaceutical Preparations><Phase><Phase 0 Trial><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Placebos><Plasma><Plasma Serum><Population><Prediction of Response to Therapy><Predisposition><Prognosis><Protein Kinase B><Proto-Oncogene Proteins c-akt><PtdIns 3-Kinase><RAC-PK protein><Radioresistance><Recurrence><Recurrent><Resectable><Residual Neoplasm><Residual Tumors><Resistance><Reticuloendothelial System, Serum, Plasma><Role><Safety><Schedule><Sham Treatment><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sporanox><Surgical><Surgical Interventions><Surgical Procedure><Survival Rate><Susceptibility><TKR1><Testing><Therapeutic Fungicides><Time><Tissue Growth><Tumor Cell><Tumor-Specific Treatment Agents><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><VEGF Receptors><VEGFR><VEGFR-2><VEGFR2><VPF Receptor><Vascular Endothelial Cell Growth Factor Receptor><Vascular Endothelial Growth Factor Receptor 2><Vascular Permeability Factor Receptor><Veterans><Xenograft><Xenograft procedure><Xenotransplantation><angiogenesis><anti-cancer drug><anti-fungal><anti-fungal agents><anti-fungal drug><arm><biological signal transduction><c-akt protein><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><cancer cell><chemo-/radio-therapy><chemo-radio-therapy><chemo-radiotherapy><chemoradiation><chemoradiation therapy><chemoradiation treatment><chemoradiotherapy><compare to control><comparison control><complete response><density><drug/agent><erbB-2 Genes><esophageal cancer patient><excision of the esophagus><exome sequencing><exome-seq><genomic biomarker><genomic marker><genomic predictors><genomic profiles><hedgehog signaling><hedgehog signaling pathway><herstatin><hh signaling pathway><improved><induction therapies><interventional strategy><metastatic esophageal><mortality><neoplastic cell><neu Genes><new drug treatments><new drugs><new marker><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel biomarker><novel drug treatments><novel drugs><novel marker><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oesophageal cancer><ontogeny><partial response><pathway><patient response><patient specific response><peripheral blood><phase 2 trial><phase II trial><precision medicine><precision-based medicine><predict therapeutic response><predict therapy response><primary end point><primary endpoint><prognostic><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><radiation resistance><radio resistance><radio-chemo-therapy><radio-chemotherapy><radiochemotherapy><related to A and C-protein><residual disease><resistant><response><response to therapy><response to treatment><responsive patient><secondary end point><secondary endpoint><sham therapy><smoothened signaling pathway><social role><standard of care><surgery><therapeutic response><therapy prediction><therapy response><treatment effect><treatment prediction><treatment response><treatment response prediction><treatment responsiveness><trial design><tumor><tumor DNA><tumor cell DNA><tumor growth><tumor-specific DNA><xeno-transplant><xeno-transplantation>