Itraconazole for Esophageal Cancer

Overseen By Thai Pham, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dallas VA Medical Center

Disqualifiers: Congestive heart failure, Pregnancy, 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: 1

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 medication, to determine if it can help treat esophageal cancer. Researchers aim to discover if itraconazole, when combined with standard treatments like chemotherapy and radiation, can improve outcomes by blocking certain cancer growth pathways. This trial targets individuals with localized esophageal or gastroesophageal junction cancer who have already undergone chemoradiation. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that itraconazole, a medicine for fungal infections, is under study for its potential to treat esophageal cancer. Early results suggest it might work by blocking certain pathways in cells that promote cancer growth. The FDA has already approved itraconazole for fungal infections, indicating its safety for those uses and providing some reassurance about its safety in humans.

No specific safety data from the studies mentioned is available regarding its use in cancer treatment. However, the trial's early phase indicates that the treatment has shown enough promise in earlier tests to warrant further study. While itraconazole is generally well-tolerated for its approved uses, monitoring for any new side effects when used for cancer is important. Researchers will closely monitor participants for any negative side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for esophageal cancer?

Itraconazole is unique because it repurposes an antifungal medication to target esophageal cancer. Unlike standard treatments like chemotherapy and radiation that directly attack cancer cells, itraconazole disrupts cancer cell growth by inhibiting a pathway crucial for their survival. Researchers are excited about this approach because it offers a potential new way to slow down or stop the progression of esophageal cancer, possibly improving outcomes for patients who have limited options.

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

Research has shown that itraconazole, a common medication for fungal infections, may help treat esophageal cancer. It blocks certain pathways, such as Hedgehog (Hh) and AKT, which are often active in these cancers. Studies have found that itraconazole can stop cancer cells from growing by targeting these pathways. It also shows promise by affecting HER2/AKT signaling, which helps cancer cells survive. In this trial, participants will receive itraconazole as an experimental treatment. Early evidence suggests that itraconazole might improve treatment results when combined with other therapies for esophageal cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

David Wang, MD, PhD

Principal Investigator

North Texas Veterans Healthcare System

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Itraconazole

Trial Overview 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.

How Is the Trial Designed?

Group I: Itraconazole Experimental Treatment 1 Intervention

Itraconazole capsule 300mg twice daily for 6-8 weeks following chemoradation.

Who Is Running the Clinical Trial?

Dallas VA Medical Center

Lead Sponsor

Trials

35

Recruited

4,800+

Published Research Related to This Trial

A systematic review of antiemetic agents for preventing chemotherapy-induced nausea and vomiting (CINV) in children found that these medications, including aprepitant and ondansetron, are generally safe with manageable adverse effects.

While the recommended antiemetics are effective, it is important to consider individual patient risk factors, particularly for rare side effects like cardiac arrhythmia, and further research is needed to assess their long-term safety in pediatric cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Patel, P., Paw Cho Sing, E., Dupuis, LL.[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]

HTX-019, an NK-1 receptor antagonist, was found to be safe for cancer patients undergoing chemotherapy, with no treatment-emergent adverse events directly related to the drug during the study.

In a retrospective analysis of 100 patients, only five reversible adverse events were reported during treatment cycles, indicating a favorable safety profile for HTX-019 as part of an antiemetic regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of antiemetic prophylaxis with HTX-019 as a 30-min infusion in patients with cancer: a retrospective study. Perry, TS., Dickson, N., Patton, JF.[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]

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]

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]

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]

HTX-019, a new injectable formulation of aprepitant, has shown a tolerable safety profile in cancer patients when administered via both a 30-minute IV infusion and a 2-minute IV injection, with no treatment-emergent adverse events occurring within 30 minutes of administration.

In a study of 135 patients undergoing chemotherapy, both administration methods were well tolerated, and while some adverse events were reported during chemotherapy, none were directly related to HTX-019, indicating its potential as a safe option for preventing chemotherapy-induced nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crossover safety study of aprepitant: 2-min injection vs 30-min infusion in cancer patients receiving emetogenic chemotherapy. Navari, RM., Mosier, MC.[2020]

In a study of 141 patients undergoing high-emetogenic chemotherapy, the OLN10 group experienced significantly less severe nausea compared to the APR group, with fewer patients reporting grades 2-4 nausea (8.7% vs. 27.7%).

The overall efficacy in preventing chemotherapy-induced nausea and vomiting (CINV) was comparable between OLN5 and APR, indicating that OLN5 may be a viable alternative for CINV prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Ithimakin, S., Theeratrakul, P., Laocharoenkiat, A., et al.[2020]

In a study of 20 head and neck cancer patients, the addition of aprepitant to a triple antiemetic regimen significantly improved the complete response rate for nausea during acute cisplatin treatment, indicating its efficacy in managing chemotherapy-induced nausea.

The study found no clinically relevant adverse reactions to aprepitant, suggesting that it is a safe option for patients undergoing daily cisplatin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of aprepitant for nausea in patients with head and neck cancer receiving daily cisplatin therapy. Ishimaru, K., Takano, A., Katsura, M., 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]

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]

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]

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/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 ...

3. 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 ...

4. 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 ...

5. 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 ...

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. withpower.com withpower.com/trial/itraconazole-for-esophageal-cancer-2a445

Itraconazole for Esophageal Cancer Itraconazole, an FDA-approved antifungal, shows significant antitumor activity against esophageal cancer by inhibiting cell proliferation and inducing cell- ...