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 or chemoimmunotherapy and surgery in the the treatment of locoregional esophageal and gastroesophageal junction cancers.
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 or perioperative chemoimmunotherapy and curative intent esophagectomy
World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 at enrollment
Adequate renal and liver function as judged by the treating physician
Inability to provide Informed Consent
New York Heart Association (NYHA) class III or IV congestive heart failure (CHF)
LFT>3X upper limit of normal
Drug allergy to itraconazole
Single group
Itraconazole
DrugItraconazole 300 milligrams po bid for two weeks prior and 6-8 weeks after completion of standard of care neoadjuvant chemoradiation (or 4-6 weeks after completion of standard of care pre-operative chemoimmunotherapy)
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.
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.
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.
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.
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.
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VA Office of Research and Development
Lead sponsor
Durham VA Health Care System
Collaborator
VA Palo Alto Health Care System
Collaborator
Portland VA Medical Center
Collaborator
VA Puget Sound Health Care System
Collaborator
Michael E. DeBakey VA Medical Center
Collaborator
VA Boston Healthcare System
Collaborator
North Texas Veterans Healthcare System
Collaborator
VA Ann Arbor Healthcare System
Collaborator
