Itraconazole for Esophageal Cancer

Recruiting at 6 trial locations

Overseen By Jonathan Dowell, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Disqualifiers: CHF, LFT>3X, Itraconazole allergy, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

78 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests itraconazole, a common anti-fungal drug, to determine if it can aid in treating esophageal cancer when combined with standard treatments like chemotherapy and surgery. Researchers aim to discover if itraconazole can improve outcomes by targeting specific cancer growth pathways. Suitable participants have esophageal cancer deemed operable by a surgeon and plan to undergo chemotherapy and radiation before surgery. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant findings.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that itraconazole is likely to be safe for humans?

Research shows that itraconazole is generally safe and well-tolerated as a treatment. This common antifungal medication has been used for other health issues, suggesting it is likely safe for most people. In studies on its use for esophageal cancer, itraconazole has shown promise in blocking certain cancer cell pathways without major safety concerns. As this trial is in Phase 2, the treatment has already passed initial safety tests in earlier stages. However, consulting a healthcare professional is always important to determine if it's the right choice. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Itraconazole is unique because, unlike the typical treatments for esophageal cancer, which often involve chemotherapy and radiation, it uses an antifungal drug that targets cancer cell growth in a new way. Researchers are particularly excited about itraconazole because it inhibits a pathway called Hedgehog signaling, which is crucial for cancer cell survival and proliferation. This mechanism offers a fresh angle in battling esophageal cancer, potentially enhancing the effectiveness of standard treatments and improving patient outcomes.

What evidence suggests that itraconazole might be an effective treatment for esophageal cancer?

Research has shown that itraconazole, a common antifungal medication, may help treat esophageal cancer. Studies have found that itraconazole can block pathways such as Hedgehog and AKT, which are often active in this cancer. By interfering with these cancer growth signals, itraconazole has demonstrated strong effects against tumors. In this trial, participants will receive itraconazole alongside standard cancer treatments like chemotherapy, radiation, and surgery. Early findings suggest that itraconazole could increase the chances of a complete response in patients. ^{1 2 4 6 7}

Who Is on the Research Team?

David H Wang, MD PhD

Principal Investigator

VA Ann Arbor Healthcare System, Ann Arbor, MI

Are You a Good Fit for This Trial?

This trial is for individuals who can consent and have been diagnosed with resectable esophageal or gastroesophageal junction cancer, planning to undergo chemoradiation and surgery. They should be relatively active (WHO/ECOG status 0-2) and have good kidney and liver function.

Inclusion Criteria

I understand the study and can agree to participate.

I can take care of myself and perform daily activities.

My kidney and liver are working well.

Exclusion Criteria

My heart's electrical cycle is longer than normal and will be monitored.

Inability to provide Informed Consent

I am allergic to the medication itraconazole.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-treatment with Itraconazole

Participants receive oral itraconazole for 2 weeks before starting standard of care neoadjuvant chemoradiation

2 weeks

1 visit (in-person)

Neoadjuvant Chemoradiation

Participants undergo standard of care neoadjuvant chemoradiation

6-8 weeks

Weekly visits (in-person)

Post-chemoradiation with Itraconazole

Participants receive oral itraconazole for 6-8 weeks after completion of chemoradiation

6-8 weeks

Bi-weekly visits (in-person)

Surgery

Participants undergo esophagectomy if no new metastases are found

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Itraconazole

Trial Overview The trial tests Itraconazole as an add-on to standard care in treating locoregional esophageal cancers. It's a phase II study, meaning it focuses on the drug's effectiveness when combined with chemotherapy, radiation therapy, and surgery.

How Is the Trial Designed?

Group I: Itraconazole Experimental Treatment 1 Intervention

Itraconazole 300 mg po bid for two weeks prior and 6-8 weeks after completion of standard of care neoadjuvant chemoradiation

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

VA Puget Sound Health Care System

Collaborator

Trials

67

Recruited

225,000+

Michael E. DeBakey VA Medical Center

Collaborator

Trials

68

Recruited

17,200+

Portland VA Medical Center

Collaborator

Trials

44

Recruited

7,800+

VA Palo Alto Health Care System

Collaborator

Trials

97

Recruited

58,500+

VA Boston Healthcare System

Collaborator

Trials

73

Recruited

971,000+

North Texas Veterans Healthcare System

Collaborator

Trials

39

Recruited

4,005,000+

VA Ann Arbor Healthcare System

Collaborator

Trials

19

Recruited

10,300+

Durham VA Health Care System

Collaborator

Trials

8

Recruited

64,900+

Published Research Related to This Trial

Biologic therapies, particularly those targeting HER2 and VEGF, are showing promise in treating esophageal and gastric cancers, with trastuzumab and ramucirumab currently recommended by the NCCN for specific patient groups.

Recent studies indicate that other agents like pertuzumab, apatinib, and pembrolizumab may improve overall and progression-free survival, suggesting a growing role for targeted biologic therapies in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. Samson, P., Lockhart, AC.[2020]

In a phase 2 trial involving 105 elderly or comorbid patients with locally advanced esophageal squamous cell carcinoma (ESCC), the combination of S-1 and radiotherapy achieved a 3-year local control rate of 61.1%, indicating its effectiveness in managing this patient population.

The treatment demonstrated low toxicity, with serious adverse events occurring in a small percentage of patients, suggesting that S-1 combined with radiotherapy is a safe option for those who cannot tolerate traditional intravenous chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Chen, Y., Zhu, Z., Zhao, W., et al.[2022]

Itraconazole, an FDA-approved antifungal, shows significant antitumor activity against esophageal cancer by inhibiting cell proliferation and inducing cell-cycle arrest, particularly affecting esophageal squamous cell carcinoma and adenocarcinoma cell lines.

The mechanism of action involves downregulation of the HER2/AKT signaling pathway, as evidenced by decreased phosphorylation of key proteins in both cell lines and mouse xenograft models, along with promising results from an early phase I clinical trial in patients with esophageal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway. Zhang, W., Bhagwath, AS., Ramzan, Z., et al.[2022]

In a study of 125 patients with unresectable squamous cell cancer of the esophagus, adding chemotherapy (cisplatin) to radiotherapy resulted in a significant improvement in median survival (13.4 months for CRT vs. 7.1 months for RT alone).

The addition of cisplatin was associated with manageable side effects, including a lower incidence of late complications such as strictures (13% in CRT vs. 28% in RT), indicating that the combination treatment is both effective and relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised trial of radiotherapy compared with cisplatin chemo-radiotherapy in patients with unresectable squamous cell cancer of the esophagus. Kumar, S., Dimri, K., Khurana, R., et al.[2013]

Neoadjuvant chemotherapy for esophageal cancer is gaining attention as it targets both the primary tumor and metastatic disease, potentially improving outcomes compared to traditional therapies like surgery or radiation.

While chemotherapy can cause significant side effects, they have been manageable, and careful monitoring has not increased the risks associated with surgery, indicating that this approach may be safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemotherapy and surgery of cancer of the esophagus. Kelsen, DP., Hilaris, B., Martini, N.[2019]

Neoadjuvant chemotherapy for esophageal cancer is gaining attention as it targets both the primary tumor and metastatic disease, potentially improving outcomes compared to traditional therapies like surgery or radiation.

Despite the significant toxicities associated with chemotherapy, they have been manageable, and careful monitoring has not increased the risks of surgery, paving the way for upcoming large-scale randomized trials to assess its impact on survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemotherapy and surgery of cancer of the esophagus. Kelsen, DP., Bains, M., Burt, M.[2019]

Itraconazole, an antifungal drug, effectively inhibits the growth and survival of esophageal cancer cells by activating AMPK signaling, which is crucial for inducing cell death.

In vivo studies demonstrated that itraconazole significantly reduced tumor growth in mice, but this effect was lost when AMPK signaling was inhibited, highlighting the importance of AMPK in its mechanism of action against esophageal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Itraconazole-Induced Inhibition on Human Esophageal Cancer Cell Growth Requires AMPK Activation. Chen, MB., Liu, YY., Xing, ZY., et al.[2020]

In a study of 26 patients with recurrent or metastatic esophageal squamous cell carcinoma who had previously failed first-line chemotherapy, the combination of anlotinib and S-1 resulted in a partial remission rate of 23.1% and a disease control rate of 69.2%.

The treatment showed a median progression-free survival of 4.5 months, with better outcomes observed in patients with moderate or high tumor differentiation, indicating that this combination therapy is a promising second-line option with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy of anlotinib plus S-1 as a second-line therapy for recurrent or metastatic esophageal squamous cell carcinoma]. Sun, W., Zou, X., Zhang, W., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8492513/

Itraconazole Exerts Its Antitumor Effect in Esophageal ... These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling. Introduction.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05563766

A Phase II Trial to Evaluate the Effect of Itraconazole on ... This study will evaluate whether the use of itraconazole leads to increased rates of pathologic complete response (pathCR) by at least 15% compared to ...

3. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/206561

Evaluating the Effect of Itraconazole on Pathologic Complete ... Esophageal cancer, which has a low 5-year overall survival rate for all stages (<20%) , is increasing in incidence. Previous studies have shown that the ...

4. ctv.veeva.com ctv.veeva.com/study/a-phase-ii-trial-to-evaluate-the-effect-of-itraconazole-on-pathologic-complete-response-rates-in-res

A Phase II Trial to Evaluate the Effect of Itraconazole on ... Esophageal cancer, which has a low 5-year overall survival rate (<20%) is increasing in incidence. Previous studies have shown that Hedgehog ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04018872

NCT04018872 | Evaluating the Effect of Itraconazole on ... Itraconazole, an antifungal agent, has been shown to inhibit the Hedgehog (Hh) and AKT signaling pathways, which are upregulated in esophageal cancer and ...

6. aacrjournals.org aacrjournals.org/mct/article/doi/10.1158/1535-7163.MCT-20-0638/673360/am/Itraconazole-Exerts-its-Anti-Tumor-Effect-in

Itraconazole Exerts its Anti-Tumor Effect in Esophageal ... These data demonstrate that itraconazole has potent anti-tumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling. This content ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS4212

Repurposing itraconazole for secondary prevention of ... Given its safety and affordability, itraconazole represents a promising strategy to reduce BE recurrence and EAC risk. Methods: This randomized, ...