An Early Phase 1 interventional study of Itraconazole in Non-small Cell Lung Cancer, sponsored by University of Texas Southwestern Medical Center. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-05-03.
Sponsored by University of Texas Southwestern Medical Center · Early Phase 1, Interventional, and Treatment
The purpose of this study is to determine the pharmacodynamics effects of itraconazole in early-stage non-small cell lung cancer.
This is a phase 0 clinical trial. While clinical data including safety will be recorded, the principal outcomes are pharmacodynamic endpoints. Specifically, the investigators seek to identify: (1) effects of itraconazole on tumor angiogenesis, (2) effects of itraconazole on the Hh pathway, (3) biomarker predictors of these effects, (4) the correlation between itraconazole pharmacokinetics and these effects, (5) the correlation between different biomarkers.
Up to 15 eligible patients with previously diagnosed or suspected NSCLC planned for resection will undergo a study-specific core needle biopsy, imaging (dynamic contrast enhanced [DCE]-, diffusion weighted imaging [DWI]-, and arterial spin labeling [ASL] magnetic resonance imaging [MRI]), skin punch biopsy, and collection of peripheral blood. Subjects will then receive itraconazole 600 mg PO daily for 7-10 days, following which they will undergo repeat imaging, skin biopsy, and blood collection. Subsequently they will undergo surgical resection. Due to the safety profile of itraconazole when used as an antifungal agent , all histologic subtypes of NSCLC will be eligible for the trial. The itraconazole dose of 600 mg, higher than an anti-angiogenic dose, has been shown to inhibit the Hedgehog (Hh) pathway.
7,243 studies on the registry are indexed under Lung Neoplasms; 1,557 are open to participants now.
This study's enrollment of 13 is below the median of 60 across 5,295 interventional studies indexed under Lung Neoplasms.
Browse Lung Neoplasms studies →University of Texas Southwestern Medical Center is the lead sponsor of 990 studies on the registry; 201 are open to participants now.
Of its 135 completed or terminated interventional studies of FDA-regulated products, 100 (74%) have results posted.
Counted across the registry records on this site, refreshed daily.
Adequate organ function as defined below:
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
6.1 A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
Exclusion Criteria:
600 mg twice daily for 10-14 days
Drug: Itraconazole
Once on study, itraconazole will be taken twice daily for a total of 10-14 days. After being on itraconazole for 7-10 days, "Post-treatment" assessments will include a skin biopsy, blood draw for the PK (pharmacokinetics) analyses and the cytokine panel, and also MRI evaluations (anticipated to last 45-50 minutes). Toxicity assessments and laboratory checks will also be conducted during that time. Following these assessments, itraconazole will be continued until the day of surgery. At the time of surgical resection, a tissue sample (with adjacent normal tissue as per standard resection technique) will be obtained to complete the analysis. Following resection, subjects will be followed per standard post-operative procedure.
Changes in Tumor Tissue Microvessel Density [MVD] From Baseline
Images of DAPI (4',6-Diamidino-2-Phenylindole) , CD31 (cluster of differentiation 31 ), and CD34 (cluster of differentiation 34) were taken from the same field of view and then merged.
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Change in HIF1α From Baseline
A commercially available kit will be used to measure HIF1α levels.
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Change in VEGFR2 From Baseline
A commercially available kit will be used to measure VEGFR2 levels.
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Change in Phospho-VEGFR2 From Baseline
A commercially available kit will be used to measure Phospho-VEGFR2 levels.
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment
The following plasma cytokines were measured using a commercially available kit.
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Mean Percent Change in Angiogenic Cytokines From Baseline
A commercially available kit will be used to measure Angiogenic Cytokines levels.
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Changes in Perfusion (Ktrans)
DCE (dynamic contrast enhanced ) MRI is an established technology to assess microvessel density (MVD) and tumor capillary permeability.
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Number of Participants With Tumor SMO (Smoothened) Gene Mutations, GLI2 and CCND1 Copy Number, PI3K-mTOR Pathway Activation
phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (PI3K-mTOR pathway )
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Change in Tumor Tissue GLI1, SHH and PTCH1 Levels From Baseline
This can be measured by analyzing frozen-treated tumor tissue for GLI1 (glioma-associated oncogene ) and PTCH1(patched-1) mRNA (Messenger Ribonucleic Acid) by qPCR.
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Change in Skin Biopsy GLI1 Levels From Baseline
We analyzed serial skin biopsies for GLI1 mRNA by qPCR (quantitative polymerase chain reaction).
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Change in Skin Biopsy SHH Levels From Baseline
We analyzed serial skin biopsies for SHH (Sonic Hedgehog )levels mRNA by qPCR.
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Change in Skin Biopsy PTCH1 Levels From Baseline
We analyzed serial skin biopsies for PTCH1 mRNA by qPCR.
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Number of Participants With Tumor Cell Proliferation/Apoptosis
Tumor proliferation and apoptosis will be assessed by tumor Ki67 and cleaved caspase 3 levels
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Itraconazole Levels in Post-treatment Serum
Itraconazole levels assessed by post-treatment serum
Time frame: Post Treatment (after 7-10 days of itraconazole bid)
Itraconazole Levels in Tumor Tissue
Itraconazole levels assessed by tumor tissue
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Itraconazole Levels in Skin Biopsy
Itraconazole levels assessed by skin biopsy
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
| Milestone | Itraconazole |
|---|---|
| Started | 13 |
| Completed | 13 |
| Not completed | 0 |
Images of DAPI (4',6-Diamidino-2-Phenylindole) , CD31 (cluster of differentiation 31 ), and CD34 (cluster of differentiation 34) were taken from the same field of view and then merged.
| Percent area fraction | Itraconazole |
|---|---|
| Changes in Tumor Tissue Microvessel Density [MVD] From Baseline | 0.005 ± 0.045 |
A commercially available kit will be used to measure HIF1α levels.
No measurements were reported for this outcome.
A commercially available kit will be used to measure VEGFR2 levels.
No measurements were reported for this outcome.
A commercially available kit will be used to measure Phospho-VEGFR2 levels.
No measurements were reported for this outcome.
The following plasma cytokines were measured using a commercially available kit.
| Percent change | Itraconazole |
|---|---|
| IL-1b | -14.4159 ± 117.2143 |
| IL-1ra | -16.9648 ± 72.1061 |
| IL-2 | -21.5999 ± 81.7471 |
| IL-4 | -5.0114 ± 36.6851 |
| IL-5 | -13.7573 ± 71.6122 |
| IL-6 | -62.5420 ± 103.4791 |
| IL-7 | -21.9919 ± 64.4562 |
| IL-9 | -0.9209 ± 56.3665 |
| IL-10 | 2.9705 ± 118.2381 |
| IL-12 | -30.0689 ± 99.9174 |
| IL-13 | -16.1310 ± 75.8152 |
| IL-15 | -27.7823 ± 92.4703 |
| IL-17 | -24.3512 ± 82.8199 |
| IP-10 | -16.7481 ± 60.9495 |
| MCP-1 | -11.3317 ± 34.8165 |
| MIP-1a | -14.7291 ± 76.0138 |
| MIP-1b | 0.0767 ± 57.2234 |
| RANTES | 5.1468 ± 128.1372 |
| TNF-a | -18.0238 ± 44.3590 |
| IFN-g | -39.7280 ± 62.7207 |
| Eotaxin | 2.8770 ± 31.7644 |
| G-CSF | -4.4567 ± 30.0457 |
| GM-CSF | -45.6701 ± 60.2840 |
A commercially available kit will be used to measure Angiogenic Cytokines levels.
| Percent change | Itraconazole |
|---|---|
| IL-8 | -4.5391 ± 124.2834 |
| PDGF-bb | 7.7116 ± 209.4990 |
| VEGF | -13.5786 ± 47.4821 |
| FGF-b | -35.5341 ± 65.0768 |
DCE (dynamic contrast enhanced ) MRI is an established technology to assess microvessel density (MVD) and tumor capillary permeability.
| min-1 | Itraconazole |
|---|---|
| Changes in Perfusion (Ktrans) | 0.008 ± 0.072 |
phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (PI3K-mTOR pathway )
No measurements were reported for this outcome.
This can be measured by analyzing frozen-treated tumor tissue for GLI1 (glioma-associated oncogene ) and PTCH1(patched-1) mRNA (Messenger Ribonucleic Acid) by qPCR.
No measurements were reported for this outcome.
We analyzed serial skin biopsies for GLI1 mRNA by qPCR (quantitative polymerase chain reaction).
| relative units | Itraconazole |
|---|---|
| Change in Skin Biopsy GLI1 Levels From Baseline | 0.27347 ± 0.54713 |
We analyzed serial skin biopsies for SHH (Sonic Hedgehog )levels mRNA by qPCR.
No measurements were reported for this outcome.
We analyzed serial skin biopsies for PTCH1 mRNA by qPCR.
| relative units | Itraconazole |
|---|---|
| Change in Skin Biopsy PTCH1 Levels From Baseline | 0.03164 ± 0.22360 |
Tumor proliferation and apoptosis will be assessed by tumor Ki67 and cleaved caspase 3 levels
No measurements were reported for this outcome.
Itraconazole levels assessed by post-treatment serum
| ng/mL | Itraconazole |
|---|---|
| Itraconazole Levels in Post-treatment Serum | 1264 ± 688 |
Itraconazole levels assessed by tumor tissue
| ng/g | Itraconazole |
|---|---|
| Itraconazole Levels in Tumor Tissue | 2585 ± 1986 |
Itraconazole levels assessed by skin biopsy
No measurements were reported for this outcome.
Collected over 10 days. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Itraconazole | 0/13 (0%) | 0/13 (0%) | 2/13 (15.4%) |
| Event | Itraconazole |
|---|---|
| NauseaGastrointestinal disorders | 2/13 |
| HeartburnGastrointestinal disorders | 1/13 |
| Non-Cardiac chest painGeneral disorders | 1/13 |
| Age, Continuous(years) | Itraconazole |
|---|---|
| Median | 64 ± 0.05 |
| Sex: Female, Male(Participants) | Itraconazole |
|---|---|
| Female | 9 |
| Male | 4 |
| Race (NIH/OMB)(Participants) | Itraconazole |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 1 |
| White | 12 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Itraconazole |
|---|---|
| United States | 13 |
| Histology(Participants) | Itraconazole |
|---|---|
| Adenocarcinoma | 9 |
| Squamous Cell | 2 |
| Other | 2 |
| Smoking History(Participants) | Itraconazole |
|---|---|
| Former | 10 |
| Never | 3 |
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University of Texas Southwestern Medical Center