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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
13
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.
UT Southwestern Medical Center
Dallas, Texas, United States
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)
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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)