Clinical trial NCT05563766: A Phase II Trial to Evaluate the Effect of Itraconazole on Pathologic Complete Response Rates in Resectable Esophageal Cancer
Official title: A Phase II Trial to Evaluate the Effect of Itraconazole on Pathologic Complete Response Rates in Resectable Esophageal Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Gastroesophageal Junction Carcinoma
Keywords: Itraconazole
Neoadjuvant
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Durham VA Health Care System
name: VA Palo Alto Health Care System
name: Portland VA Medical Center
name: VA Puget Sound Health Care System
name: Michael E. DeBakey VA Medical Center
name: VA Boston Healthcare System
name: North Texas Veterans Healthcare System
name: VA Ann Arbor Healthcare System
First posted: 2022-10-03
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
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.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Rate of pathological complete response with itraconazole
timeFrame: 20 weeks
Secondary outcomes:
measure: Comparison of Hedgehog, AKT, and angiogenesis pathway status before and after intervention
timeFrame: 20 weeks
measure: Correlation of peripheral blood and esophageal tissue levels of itraconazole and hydroxyitraconazole with pathologic response
timeFrame: 20 weeks
measure: Develop a predictive genomic profile of treatment response
timeFrame: 20 weeks
measure: Determine the utility of ctDNA and exosome characterization as a prognostic marker
timeFrame: 20 weeks
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System, Ann Arbor, MI
state: Michigan
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System Seattle Division, Seattle, WA
state: Washington
Study officials:
affiliation: VA Ann Arbor Healthcare System, Ann Arbor, MI
name: David H Wang, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.