Itraconazole for Esophageal Cancer
Recruiting in Palo Alto (17 mi)
Overseen byDavid Wang, MD, PhD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Dallas VA Medical Center
Disqualifiers: Congestive heart failure, Pregnancy, others
Stay on Your Current Meds
No Placebo Group
Prior Safety Data
Approved in 4 Jurisdictions
Trial Summary
What is the purpose of this trial?This trial tests if itraconazole, a drug for fungal infections, can help treat esophageal cancer. It targets patients with poor survival rates. The drug works by blocking growth signals in cancer cells. The trial will see if adding itraconazole after standard treatment improves outcomes. Itraconazole is an FDA-approved antifungal agent that has shown promising anticancer activities in recent years.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the drug itraconazole for esophageal cancer?
Research shows that itraconazole, a drug usually used to treat fungal infections, can slow down the growth of esophageal cancer cells by blocking certain proteins (HER2/AKT) that help cancer cells grow. It also activates a process (AMPK signaling) that leads to cancer cell death, which has been observed in both lab studies and early clinical trials.
12345Is Itraconazole safe for use in humans?
There is no specific safety data for Itraconazole in the provided research articles, but it is generally considered safe for use in humans for various conditions, including fungal infections, when prescribed by a healthcare professional.
678910How does the drug itraconazole differ from other treatments for esophageal cancer?
Itraconazole, originally an antifungal drug, is unique in treating esophageal cancer by blocking the HER2/AKT signaling pathway, which is involved in cancer cell growth, and activating AMPK signaling, leading to cancer cell death. This dual action is different from traditional chemotherapy or surgery, offering a novel approach to targeting cancer cells.
23111213Eligibility Criteria
This trial is for individuals with localized esophageal or gastroesophageal junction cancer. Participants must be able to consent, have normal heart rhythm (QTc ≤450ms), no severe heart failure history, liver function tests within three times the upper limit of normal, and not be pregnant or allergic to itraconazole.Inclusion Criteria
My esophageal cancer has not spread beyond the local area.
My cancer is located at the junction of the stomach and esophagus.
Exclusion Criteria
Patients with QTc>450ms
Patients unwilling or unable to provide informed consent
You are allergic to itraconazole.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Neoadjuvant Chemoradiation
Participants undergo 5-6 weeks of standard of care neoadjuvant chemoradiation
5-6 weeks
Weekly visits (in-person)
Itraconazole Treatment
Participants receive itraconazole 300 mg twice daily for 6-8 weeks
6-8 weeks
Bi-weekly visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including esophagectomy and analysis of tissue samples
3-4 months
Monthly visits (in-person)
Participant Groups
The study is testing if Itraconazole can improve outcomes when given before standard chemoradiation therapy in treating esophageal and gastroesophageal junction cancers. It's a phase II trial focusing on how this anti-fungal drug affects cancer pathways.
1Treatment groups
Experimental Treatment
Group I: ItraconazoleExperimental Treatment1 Intervention
Itraconazole capsule 300mg twice daily for 6-8 weeks following chemoradation.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Dallas VA Medical CenterDallas, TX
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Who Is Running the Clinical Trial?
Dallas VA Medical CenterLead Sponsor
References
A randomised trial of radiotherapy compared with cisplatin chemo-radiotherapy in patients with unresectable squamous cell cancer of the esophagus. [2013]Following our phase II experience, a randomised trial was undertaken to evaluate the efficacy of adding chemotherapy to radiotherapy in patients with unresectable squamous cell cancer of the esophagus.
Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway. [2022]Itraconazole, an FDA-approved antifungal, has antitumor activity against a variety of cancers. We sought to determine the effects of itraconazole on esophageal cancer and elucidate its mechanism of action. Itraconazole inhibited cell proliferation and induced G1-phase cell-cycle arrest in esophageal squamous cell carcinoma and adenocarcinoma cell lines. Using an unbiased kinase array, we found that itraconazole downregulated protein kinase AKT phosphorylation in OE33 esophageal adenocarcinoma cells. Itraconazole also decreased phosphorylation of downstream ribosomal protein S6, transcriptional expression of the upstream receptor tyrosine kinase HER2, and phosphorylation of upstream PI3K in esophageal cancer cells. Lapatinib, a tyrosine kinase inhibitor that targets HER2, and siRNA-mediated knockdown of HER2 similarly suppressed cancer cell growth in vitro Itraconazole significantly inhibited growth of OE33-derived flank xenografts in mice with detectable levels of itraconazole and its primary metabolite, hydroxyitraconazole, in esophagi and tumors. HER2 total protein and phosphorylation of AKT and S6 proteins were decreased in xenografts from itraconazole-treated mice compared to xenografts from placebo-treated mice. In an early phase I clinical trial (NCT02749513) in patients with esophageal cancer, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling.
Itraconazole-Induced Inhibition on Human Esophageal Cancer Cell Growth Requires AMPK Activation. [2020]We here evaluated the antiesophageal cancer cell activity by the antifungal drug itraconazole. Our results show that μg/mL concentrations of itraconazole potently inhibited survival and proliferation of established (TE-1 and Eca-109) and primary human esophageal cancer cells. Itraconazole activated AMPK signaling, which was required for subsequent esophageal cancer cell death. Pharmacologic AMPK inhibition, AMPKα1 shRNA, or dominant negative mutation (T172A) almost completely abolished itraconazole-induced cytotoxicity against esophageal cancer cells. Significantly, itraconazole induced AMPK-dependent autophagic cell death (but not apoptosis) in esophageal cancer cells. Furthermore, AMPK activation by itraconazole induced multiple receptor tyrosine kinases (RTKs: EGFR, PDGFRα, and PDGFRβ), lysosomal translocation, and degradation to inhibit downstream Akt activation. In vivo, itraconazole oral gavage potently inhibited Eca-109 tumor growth in SCID mice. It was yet ineffective against AMPKα1 shRNA-expressing Eca-109 tumors. The in vivo growth of the primary human esophageal cancer cells was also significantly inhibited by itraconazole administration. AMPK activation, RTK degradation, and Akt inhibition were observed in itraconazole-treated tumors. Together, itraconazole inhibits esophageal cancer cell growth via activating AMPK signaling. Mol Cancer Ther; 17(6); 1229-39. ©2018 AACR.
[Clinical efficacy of anlotinib plus S-1 as a second-line therapy for recurrent or metastatic esophageal squamous cell carcinoma]. [2021]To investigate the efficacy of anlotinib plus S-1 for treatment of patients with recurrent or metastatic esophageal squamous cell carcinoma with failed first-line chemotherapy.
Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. [2020]Biologic agents, including targeted antibodies as well as immunomodulators, are demonstrating unparalleled development and study across the entire spectrum of human malignancy. This review summarizes the current state of biologic therapies for esophageal, esophagogastric, and gastric malignancies, including those that target human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-Met, mechanistic target of rapamycin (mTOR) and immunomodulators. We focus primarily on agents that have been included in phase II and III clinical trials in locally advanced, progressive, or metastatic esophageal and gastric malignancies. At this time, only two biologic therapies are recommended by the National Comprehensive Cancer Network (NCCN): trastuzumab for patients with esophageal/esophagogastric or gastric adenocarcinomas with HER2 overexpression and ramucirumab, a VEGFR-2 inhibitor, as a second-line therapy for metastatic disease. However, recent reports of increases in overall and progression-free survival for agents including pertuzumab, apatinib, and pembrolizumab will likely increase the use of targeted biologic therapy in clinical practice for esophageal and gastric malignancies.
Crossover safety study of aprepitant: 2-min injection vs 30-min infusion in cancer patients receiving emetogenic chemotherapy. [2020]Introduction: HTX-019 (CINVANTI®) is a novel injectable emulsion formulation of the neurokinin 1 receptor antagonist (RA) aprepitant, approved for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). HTX-019 has demonstrated a tolerable safety profile when administered via 30-min intravenous (IV) infusion and 2-min IV injection in healthy volunteers. This prospective study evaluated the safety of HTX-019 administered via 30-min IV infusion and 2-min injection (IV push) in patients with cancer. Materials and methods: This prospective single-center, randomized, safety, 2-sequence, 2-period, crossover study evaluated HTX-019 130 mg within a guideline-recommended 3-drug regimen for CINV prophylaxis in patients receiving highly (HEC) or moderately emetogenic chemotherapy (MEC). Treatment-emergent adverse events (TEAEs) were assessed at 0-30 (primary endpoint), 30-60, and >60 mins (chemotherapy administration period) following the initiation of the HTX-019 administration, focusing on infusion-site adverse events and hypersensitivity reactions (dyspnea, anaphylaxis). Results: Among 135 patients (35 MEC, 100 HEC), the most common diagnoses were ovarian (32), lung (17), endometrial (17), and colorectal (15) cancer. Patients were randomized 1:1 to a 2-min injection and a 30-min infusion of HTX-019 (sequence AB or BA), followed by a 5-hydroxytryptamine type 3 RA IV (palonosetron 0.25 mg for 30 s or ondansetron 8-16 mg for 5-10 mins), dexamethasone IV (8-12 mg for 15 mins), and the chemotherapy regimen. Both administration methods were generally well tolerated. No TEAEs occurred within 30 mins after start of HTX-019 administration. All TEAEs occurred during chemotherapy administration; 2 patients experienced 2 TEAEs following injection, and 5 experienced 8 TEAEs following infusion. Three adverse events following infusion (2 dyspnea, 1 throat closing) were considered serious. No TEAEs were considered related to HTX-019. Conclusion: Short injection of HTX-019 has a tolerable safety profile in patients with cancer, and represents an alternative method of HTX-019 administration for CINV prevention.
Safety of antiemetic prophylaxis with HTX-019 as a 30-min infusion in patients with cancer: a retrospective study. [2020]Aim: The NK-1 receptor antagonist HTX-019 (CINVANTI® [aprepitant injectable emulsion]) was approved for preventing chemotherapy-induced nausea and vomiting based on bioequivalence studies in healthy volunteers. The objective of this study was to evaluate HTX-019 safety in cancer patients. Patients & methods: This retrospective analysis evaluated the safety of HTX-019 130 mg 30-min intravenous infusion, as part of a three-drug antiemetic regimen. Results: No treatment-emergent adverse events (TEAEs) were deemed related to HTX-019. During treatment cycles, three of 100 patients developed five reversible TEAEs: dyspnea, hot flash, pain, nausea and visual disturbance. Between cycles, six patients had TEAEs of dizziness (three patients), infusion-site events (two patients) and headache (two patients). Conclusion: HTX-019 is safe in cancer patients receiving chemotherapy.
Safety of clinical practice guideline-recommended antiemetic agents for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric patients: a systematic review and meta-analysis. [2019]Chemotherapy-induced nausea and vomiting (CINV) are among the most distressing and feared treatment-related adverse effects for cancer patients. Selection of antiemetic agents to prevent CINV should be based on an evaluation of their efficacy and safety. This systematic review and meta-analysis describes the adverse effects associated with antiemetic agents recommended for the prevention of acute CINV in children by clinical practice guidelines (CPGs). Areas covered: A systematic literature search was conducted using four databases to identify papers describing adverse effects in pediatric patients receiving aprepitant, dexamethasone, granisetron, ondansetron, palonosetron, or tropisetron. Meta-analysis was conducted for adverse effects reported in at least three prospective studies with a cumulative incidence of at least 1%. Expert opinion: Antiemetic agents currently recommended by CPGs are relatively safe to use in children. The presence of patient-specific risk factors for rare adverse effects, especially cardiac arrhythmia, should be evaluated when selecting a patient's antiemetic therapy. Evaluation of the long-term safety of CPG-recommended antiemetic agents in pediatric cancer patients is needed.
Randomized, double-blind, placebo-controlled study of aprepitant versus two dosages of olanzapine with ondansetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving high-emetogenic chemotherapy. [2020]We assessed the efficacy of aprepitant (APR) or 10 or 5 mg OLN (OLN10 or OLN5) plus ondansetron and dexamethasone for chemotherapy-induced nausea/vomiting (CINV) prophylaxis in patients receiving high-emetogenic chemotherapy (HEC).
Efficacy of aprepitant for nausea in patients with head and neck cancer receiving daily cisplatin therapy. [2022]Although efficacy of aprepitant for suppressing emesis associated with single-dose cisplatin has been demonstrated, there are limited data on the antiemetic effect of this oral neurokinin-1 receptor antagonist during daily administration of cisplatin. Accordingly, we investigated the efficacy and safety of aprepitant in patients with head and neck cancer (HNC) receiving combination therapy with cisplatin and 5-FU (FP therapy).
Neoadjuvant chemotherapy and surgery of cancer of the esophagus. [2019]Neoadjuvant, or preoperative, chemotherapy for esophageal cancer has become an area of increasing interest because of the failure of conventional therapy (surgery or radiation) to improve disease-free or overall survival. Several autopsy series have demonstrated that, in many symptomatic western patients, esophageal cancer is a systemic disease. Neoadjuvant chemotherapy thus, in theory, allows a simultaneous attack on both the primary and metastatic disease. A number of single-arm, phase II multimodality trials have been completed. Toxicities of chemotherapy, while substantial, have been tolerable. With careful attention to detail, operative morbidity and mortality has not been increased. Large-scale randomized trials are needed to evaluate the impact of this technique on disease-free and overall survival.
Neoadjuvant chemotherapy and surgery of cancer of the esophagus. [2019]Neoadjuvant, or pre-operative, chemotherapy for esophageal cancer has become an area of increasing interest because of the failure of conventional therapy (surgery or radiation) to improve disease-free or overall survival. Several autopsy series have demonstrated that, in many symptomatic Western patients, esophageal cancer is a systemic disease. Neoadjuvant chemotherapy thus, in theory, allows a simultaneous attack on both the primary and metastatic disease. A number of single-arm, phase II multi-modality trials have been completed. Toxicities of chemotherapy, while substantial, have been tolerable. With careful attention to detail, operative morbidity and mortality has not been increased. Large-scale randomized trials, needed to evaluate the impact of this technique on disease-free and overall survival, have been designed and will shortly be activated.
Long-Term Results of a Phase 2 Study of Definitive Chemoradiation Therapy Using S-1 for Esophageal Squamous Cell Carcinoma Patients Who Were Elderly or With Serious Comorbidities. [2022]The optimal evidence-based management for the subsets of locally advanced esophageal squamous cell carcinoma (ESCC) patients who rejected or were intolerant to intravenous chemotherapy due to old age or serious comorbidities is currently lacking. This study aimed to assess the safety and local control rate (LCR) of S-1 (tegafur-gimeracil-oteracil potassium) combined with radiotherapy in these subsets of ESCC patients.