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

Sponsor

VA Office of Research and Development (U.S. Fed)

Overall Status

Not yet recruiting

CT.gov ID

NCT05563766

Collaborator

Durham VA Health Care System (U.S. Fed), VA Palo Alto Health Care System (U.S. Fed), Portland VA Medical Center (U.S. Fed), VA Puget Sound Health Care System (U.S. Fed), Michael E. DeBakey VA Medical Center (U.S. Fed), VA Boston Healthcare System (U.S. Fed)

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Adenocarcinoma Esophageal Squamous Cell Carcinoma Gastroesophageal Junction Carcinoma	Drug: Itraconazole	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

78 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Single arm, patients will receive itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after standard of care neoadjuvant chemoradiation.Single arm, patients will receive itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after standard of care neoadjuvant chemoradiation.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Apr 15, 2023

Anticipated Primary Completion Date :

Apr 14, 2028

Anticipated Study Completion Date :

Dec 14, 2029

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Rate of pathological complete response with itraconazole [20 weeks]
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.

Secondary Outcome Measures

Comparison of Hedgehog, AKT, and angiogenesis pathway status before and after intervention [20 weeks]
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 [20 weeks]
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 [20 weeks]
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 [20 weeks]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Palo Alto Health Care System, Palo Alto, CA	Palo Alto	California	United States	94304-1290
2	Durham VA Medical Center, Durham, NC	Durham	North Carolina	United States	27705
3	VA Portland Health Care System, Portland, OR	Portland	Oregon	United States	97239
4	VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX	Dallas	Texas	United States	75216
5	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas	United States	77030
6	VA Puget Sound Health Care System Seattle Division, Seattle, WA	Seattle	Washington	United States	98108