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 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.

Is 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. ^{1 2 3 4 5}

How 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. ^{6 7 8 9 10}

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. ^{6 8 11 12 13}

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

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. Ireland 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. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Itraconazole-Induced Inhibition on Human Esophageal Cancer Cell Growth Requires AMPK Activation. [2020]

4. China 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]. [2021]

5. China pubmed.ncbi.nlm.nih.gov

Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

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

7. England pubmed.ncbi.nlm.nih.gov

Safety of antiemetic prophylaxis with HTX-019 as a 30-min infusion in patients with cancer: a retrospective study. [2020]

8. England 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. [2019]

9. Germany 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. [2020]

10. Thailand pubmed.ncbi.nlm.nih.gov

Efficacy of aprepitant for nausea in patients with head and neck cancer receiving daily cisplatin therapy. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemotherapy and surgery of cancer of the esophagus. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemotherapy and surgery of cancer of the esophagus. [2019]

13. Switzerland 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. [2022]