Anti fungals are being researched as repurposed drug against cancer; Itraconazole in particular
Itraconazole as a Repurposed Drug in
Cancer: Clinical Trials and Case Reports with Dosing Protocols
Executive Summary
This report presents a comprehensive review of itraconazole as a repurposed drug in cancer treatment, focusing specifically on case reports and clinical trials with their
associated dosing protocols. Itraconazole, a common triazole anti-fungal drug in
widespread clinical use, has demonstrated potential anticancer activity through
multiple mechanisms, including inhibition of angiogenesis, Hedgehog pathway
inhibition, and reversal of multi-drug resistance.
The research identified several clinical trials and case reports across various cancer
types, including basal cell carcinoma, prostate cancer, non-small cell lung cancer,
pancreatic adenocarcinoma, and ovarian cancer. Dosing protocols varied by cancer type
and study design, with doses ranging from 100 mg to 600 mg daily, administered for
periods from 21 days to 9 months.
General Dosing Information for Itraconazole
Itraconazole is most commonly administered orally, either as 100 mg or 200 mg capsules
or as oral solution. It can also be administered intravenously, though this route is less
commonly used in cancer applications. In standard antifungal treatment, dosing varies
by indication, generally in the range of 100 mg–600 mg daily, for between one to 30 days.
For long-term maintenance or prophylaxis, dosing ranges from 100-400 mg daily.
Clinical Trials and Case Reports with Dosing Protocols
Basal Cell Carcinoma
Kim DJ, et al. 2014 (Phase II trial)
High-dose: 200 mg twice daily for 4 weeks (n=15)
Low-dose: 100 mg twice daily for average of 2.3 months (n=4)•
Results: Cell proliferation reduced by 45% (P=0.04), GLI1 mRNA reduced by 65%
(P=0.028) in high-dose. Tumor area reduced by 24% with both doses.
Prostate Cancer
Antonarakis ES, et al. 2013 (Phase II trial)
Low-dose arm: 200 mg/day until disease progression or toxicity
High-dose arm: 600 mg/day until disease progression or toxicity
Results: PSA response in high-dose: 14.3% (4-32.7%). Progression-free survival:
Low-dose 11.9 weeks (median), High-dose 35.9 weeks.
Note: The low-dose arm closed early after accruing 17 patients due to futility. High-
dose arm completed with 29 patients.
Toxicity: Greater in high-dose arm, with fatigue, nausea, anorexia, rash, and
hypokalemia. 14% of high-dose patients discontinued due to toxicity.
Suzman DL, Antonarakis ES. 2014 (Case report)
Dose: 300 mg twice daily
Duration: Treatment stopped after 5 months due to elevated bilirubin levels
Results: >50% reduction of PSA level after 12 weeks with no significant change in
testosterone level
Non-Small Cell Lung Cancer
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Rudin CM, et al. 2013 (Phase II trial)
Dose: 200 mg daily for 21 days combined with IV pemetrexed
Results: Disease stabilization at 3 months: 67% with itraconazole vs 29% without
Progression-free survival: 5.5 months with itraconazole vs 2.8 months without
(P=0.089)
Overall survival: 32 months with itraconazole vs 8 months without (P=0.012)
Pancreatic Cancer
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Ovarian Cancer
Lockhart NR, et al. 2016 (Case report)
Dose: 200 mg daily for 9 months
Results: Tumor size reduced and resected, no recurrence of disease following
surgery
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Tsubamoto H, et al. 2014 (Retrospective analysis – Recurrent clear cell ovarian
carcinoma)•
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Dose: 400 mg daily on days 2 to +2 with docetaxel and carboplatin-based
chemotherapy on day 1
Schedule: Regimen repeated every 2 weeks
Results: Response rate of 44% (95% CI, 12.77%)
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Tsubamoto H, et al. 2014 (Retrospective analysis – Resistant ovarian cancer)
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Dose: 400-600 mg daily on days 2 to +2 alongside 2nd line chemotherapy
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Results: Overall response rate of 18% (95% CI, 8.28%). 32% in treated group vs 11%
in control group.
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Progression-free survival: 103 days (median) in treated group vs 53 days in controls
(P=0.014)
Leukemia
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Vreugdenhil et al. (Clinical trial in neutropenic leukemia patients)
Used as anti-fungal prophylactic in neutropenic leukemia patients treated with
daunorubicin
Results: In ALL patients, disease-free survival tended to be longer in the ITZ group
compared to control (P < 0.06)
Pharmacokinetics Relevant to Cancer Treatment
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A single 200 mg dose produces an average peak plasma concentration of 239 ng/
mL (0.34μM) within 4.5 hours
At steady state (after 14 days of 200 mg every 12 hours), the average plasma
concentration is 1881 ng/mL (2.67 μM)
The oral solution has approximately 30% greater overall bioavailability compared
to capsule form
Plasma half-life of 200 mg capsule form is 24 hours at steady state
As a highly lipophilic molecule, ITZ has high affinity for tissues, achieving
concentrations two to ten times higher than those in plasma
Mechanisms of Action in Cancer
Itraconazole has demonstrated several mechanisms of action that contribute to its
anticancer effects:
1.
Hedgehog Pathway Inhibition: Itraconazole inhibits the Hedgehog signaling
pathway by acting directly on the Smoothened (SMO) protein, but at a different
binding site than other Hedgehog inhibitors like vismodegib.2.
3.
4.
Anti-angiogenic Activity: At clinically relevant doses, itraconazole has potent anti-
angiogenic activity, inhibiting endothelial cell proliferation and new vessel
formation.
Reversal of Multi-drug Resistance: Itraconazole can reverse chemoresistance
mediated by P-glycoprotein and other drug resistance mechanisms.
Autophagic Growth Arrest: Itraconazole may induce autophagic growth arrest in
cancer cells, possibly through inhibition of the AKT-mTOR pathway.
Conclusions and Recommendations
Based on the clinical trials and case reports reviewed, itraconazole shows promising
anticancer activity across multiple cancer types. The most common dosing protocols
include:
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For basal cell carcinoma: 200 mg twice daily for 4 weeks or 100 mg twice daily for
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2-3 months
For prostate cancer: 600 mg daily appears more effective than 200 mg daily
For non-small cell lung cancer: 200 mg daily for 21 days in combination with
chemotherapy
chemotherapy
For ovarian cancer: 400-600 mg daily on specific days in combination with
The evidence suggests that itraconazole warrants further clinical investigation as an
anticancer agent, particularly in combination with other therapies. The repurposing of
this well-established antifungal drug offers potential advantages in terms of known
safety profile and pharmacokinetics.
References
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3.
Pounds R, Leonard S, Dawson C, Kehoe S. Repurposing itraconazole for the
treatment of cancer. Oncol Lett. 2017;14(3):2587-2597. doi:10.3892/ol.2017.6569
Pantziarka P, Sukhatme V, Bouche G, Meheus L, Sukhatme VP. Repurposing Drugs in
Oncology (ReDO)—itraconazole as an anti-cancer agent. Ecancermedicalscience.
2015;9:521. doi:10.3332/ecancer.2015.521
Kim DJ, Kim J, Spaunhurst K, et al. Open-label, exploratory phase II trial of oral
itraconazole for the treatment of basal cell carcinoma. J Clin Oncol. 2014;32(8):
745-751. doi:10.1200/JCO.2013.49.95254.
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Antonarakis ES, Heath EI, Smith DC, et al. Repurposing itraconazole as a treatment
for advanced prostate cancer: a noncomparative randomized phase II trial in men
with metastatic castration-resistant prostate cancer. Oncologist. 2013;18(2):
163-173. doi:10.1634/theoncologist.2012-314
Suzman DL, Antonarakis ES. High-dose itraconazole as a noncastrating therapy for
a patient with biochemically recurrent prostate cancer. Clin Genitourin Cancer.
2014;12(2):e51-e53. doi:10.1016/j.clgc.2013.11.015
Rudin CM, Brahmer JR, Juergens RA, et al. Phase 2 study of pemetrexed and
itraconazole as second-line therapy for metastatic nonsquamous non-small-cell
lung cancer. J Thorac Oncol. 2013;8(5):619-623. doi:10.1097/JTO.
0b013e31828c3950
Lockhart NR, Waddell JA, Schrock NE, et al. Itraconazole therapy in a pancreatic
adenocarcinoma patient: A case report. J Oncol Pharm Pract. 2016;22(3):528-532.
doi:10.1177/1078155215572931
Tsubamoto H, Sonoda T, Yamasaki M, Inoue K. Impact of combination
chemotherapy with itraconazole on survival of patients with refractory ovarian
cancer. Anticancer Res. 2014;34(5):2481-2487.
Vreugdenhil G, Van Dijke BJ, Donnelly JP, et al. Efficacy of itraconazole in the
prevention of fungal infections among neutropenic patients with hematologic
malignancies and intensive chemotherapy. A double blind, placebo controlled
study. Leuk Lymphoma. 1993;11(5-6):353-358. doi:10.3109/10428199309067928
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