Non-small Cell Lung Cancer
Conditions
Brief summary
The purpose of this study is to determine the pharmacodynamics effects of itraconazole in early-stage non-small cell lung cancer.
Detailed description
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.
Interventions
DRUGItraconazole
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.
Sponsors
United States Department of Defense
University of Texas Southwestern Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically proven NSCLC planned for surgical resection. All NSCLC histologic subtypes are eligible. Alternatively, patients in whom a diagnosis of NSCLC is highly suspected based on history and imaging studies and who are, therefore, scheduled for diagnostic biopsy and/or surgical resection will also be eligible for screening, enrollment, and study treatment if they meet all additional eligibility criteria. In the event that biopsies do not confirm NSCLC, such patients will be removed from study but monitored for any adverse events resulting from study participation. 2. No prior therapy but planned for surgical resection 3. Age ≥ 18 years. 4. ECOG (Eastern Cooperative Oncology Group) 0-2 performance status 5. Adequate organ function as defined below: * total bilirubin within normal institutional limits * AST (Aspartate Aminotransferase) (SGOT)/ALT (Alanine Aminotransferase) (SPGT) ≤ 2.5 X institutional upper limit of normal * creatinine ≤ 2 X institutional upper limit of normal 6. 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: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 7. Ability to understand and willingness to sign a written informed consent.
Exclusion criteria
1. Subjects may not be receiving any investigational agents that would confound interpretation of study pharmacodynamic endpoints. 2. History of allergic reactions attributed to itraconazole or to compounds of similar chemical or biologic composition to itraconazole. 3. Uncontrolled, concurrent medical illness. 4. Active hepatitis or symptomatic liver disease. 5. History of or current evidence of uncontrolled cardiac ventricular dysfunction (congestive heart failure) or NYHA (New York Heart Association) Class III or IV heart failure. 6. Current use of medications significantly affecting metabolism of itraconazole (certain anti-convulsants, corticosteroids). See 3.5 Drug Interactions in protocol. 7. Current evidence of hyperthyroidism (which would increase metabolism of itraconazole). 8. Pregnant or lactating female or any female trying to get pregnant. 9. Claustrophobia that would interfere with MRI studies anticipated to last 45-50 minutes. 10. Metal implants deemed at risk for migration during MRI studies. 11. CrCl (Creatinine clearance) \< 45 mL/min (increased risk of nephrogenic systemic fibrosis \[NSF\] from MRI Gadolinium contrast). 12. Known allergy to MRI contrast.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Tumor Tissue Microvessel Density [MVD] From Baseline | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in HIF1α From Baseline | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | A commercially available kit will be used to measure HIF1α levels. |
| Change in VEGFR2 From Baseline | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | A commercially available kit will be used to measure VEGFR2 levels. |
| Change in Phospho-VEGFR2 From Baseline | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | A commercially available kit will be used to measure Phospho-VEGFR2 levels. |
| Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | The following plasma cytokines were measured using a commercially available kit. |
| Mean Percent Change in Angiogenic Cytokines From Baseline | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | A commercially available kit will be used to measure Angiogenic Cytokines levels. |
| Changes in Perfusion (Ktrans) | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | DCE (dynamic contrast enhanced ) MRI is an established technology to assess microvessel density (MVD) and tumor capillary permeability. |
| Change in Tumor Tissue GLI1, SHH and PTCH1 Levels From Baseline | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | 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. |
| Number of Participants With Tumor SMO (Smoothened) Gene Mutations, GLI2 and CCND1 Copy Number, PI3K-mTOR Pathway Activation | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (PI3K-mTOR pathway ) |
| Change in Skin Biopsy SHH Levels From Baseline | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | We analyzed serial skin biopsies for SHH (Sonic Hedgehog )levels mRNA by qPCR. |
| Change in Skin Biopsy PTCH1 Levels From Baseline | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | We analyzed serial skin biopsies for PTCH1 mRNA by qPCR. |
| Number of Participants With Tumor Cell Proliferation/Apoptosis | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | Tumor proliferation and apoptosis will be assessed by tumor Ki67 and cleaved caspase 3 levels |
| Itraconazole Levels in Post-treatment Serum | Post Treatment (after 7-10 days of itraconazole bid) | Itraconazole levels assessed by post-treatment serum |
| Itraconazole Levels in Tumor Tissue | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | Itraconazole levels assessed by tumor tissue |
| Itraconazole Levels in Skin Biopsy | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | Itraconazole levels assessed by skin biopsy |
| Change in Skin Biopsy GLI1 Levels From Baseline | Baseline and Post Treatment (after 7-10 days of itraconazole bid) | We analyzed serial skin biopsies for GLI1 mRNA by qPCR (quantitative polymerase chain reaction). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Itraconazole 600 mg twice daily for 10-14 days
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 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. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Itraconazole |
|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 0.05 |
| Histology Adenocarcinoma | 9 Participants |
| Histology Other | 2 Participants |
| Histology Squamous Cell | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 4 Participants |
| Smoking History Former | 10 Participants |
| Smoking History Never | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 2 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
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)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itraconazole | Changes in Tumor Tissue Microvessel Density [MVD] From Baseline | 0.005 Percent area fraction | Standard Deviation 0.045 |
Secondary
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)
Population: We did not collect this data as we did not perform this assay.
Secondary
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)
Population: We did not collect this data as we did not perform this assay.
Secondary
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)
Population: Participant with missing data were excluded from the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itraconazole | Change in Skin Biopsy GLI1 Levels From Baseline | 0.27347 relative units | Standard Deviation 0.54713 |
Secondary
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)
Population: Participant with missing data were excluded from the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itraconazole | Change in Skin Biopsy PTCH1 Levels From Baseline | 0.03164 relative units | Standard Deviation 0.2236 |
Secondary
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)
Population: SHH levels were not measured.
Secondary
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)
Population: The lab tests were not feasible with tumor tissues as they were not enough to conduct these tests.
Secondary
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)
Population: We did not collect this data as we did not perform this assay.
Secondary
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)
Population: Reasons that enrolled patients did not complete paired research MRI scans included presence of metal implants, inadequate renal function, and patient preference
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itraconazole | Changes in Perfusion (Ktrans) | 0.008 min-1 | Standard Deviation 0.072 |
Secondary
Itraconazole Levels in Post-treatment Serum
Itraconazole levels assessed by post-treatment serum
Time frame: Post Treatment (after 7-10 days of itraconazole bid)
Population: The 2 missing cases not included in this analysis here were due to inability to collect the follow-up sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itraconazole | Itraconazole Levels in Post-treatment Serum | 1264 ng/mL | Standard Deviation 688 |
Secondary
Itraconazole Levels in Skin Biopsy
Itraconazole levels assessed by skin biopsy
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Population: We have not measured itraconazole level in skin biopsy.
Secondary
Itraconazole Levels in Tumor Tissue
Itraconazole levels assessed by tumor tissue
Time frame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Population: The 4 missing cases not included in this analysis here were due to inability to collect the follow-up sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itraconazole | Itraconazole Levels in Tumor Tissue | 2585 ng/g | Standard Deviation 1986 |
Secondary
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)
Population: The 2 missing cases not included in this analysis here were due to inability to collect the follow-up sample.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Itraconazole | Mean Percent Change in Angiogenic Cytokines From Baseline | IL-8 | -4.5391 Percent change | Standard Error 124.2834 |
| Itraconazole | Mean Percent Change in Angiogenic Cytokines From Baseline | PDGF-bb | 7.7116 Percent change | Standard Error 209.499 |
| Itraconazole | Mean Percent Change in Angiogenic Cytokines From Baseline | VEGF | -13.5786 Percent change | Standard Error 47.4821 |
| Itraconazole | Mean Percent Change in Angiogenic Cytokines From Baseline | FGF-b | -35.5341 Percent change | Standard Error 65.0768 |
Secondary
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)
Population: The 2 missing cases not included in this analysis here were due to inability to collect the follow-up sample.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-1b | -14.4159 Percent change | Standard Error 117.2143 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-1ra | -16.9648 Percent change | Standard Error 72.1061 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-2 | -21.5999 Percent change | Standard Error 81.7471 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-4 | -5.0114 Percent change | Standard Error 36.6851 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-5 | -13.7573 Percent change | Standard Error 71.6122 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-6 | -62.5420 Percent change | Standard Error 103.4791 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-7 | -21.9919 Percent change | Standard Error 64.4562 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-9 | -0.9209 Percent change | Standard Error 56.3665 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-10 | 2.9705 Percent change | Standard Error 118.2381 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-12 | -30.0689 Percent change | Standard Error 99.9174 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-13 | -16.1310 Percent change | Standard Error 75.8152 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-15 | -27.7823 Percent change | Standard Error 92.4703 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IL-17 | -24.3512 Percent change | Standard Error 82.8199 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IP-10 | -16.7481 Percent change | Standard Error 60.9495 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | MCP-1 | -11.3317 Percent change | Standard Error 34.8165 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | MIP-1a | -14.7291 Percent change | Standard Error 76.0138 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | MIP-1b | 0.0767 Percent change | Standard Error 57.2234 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | RANTES | 5.1468 Percent change | Standard Error 128.1372 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | TNF-a | -18.0238 Percent change | Standard Error 44.359 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | IFN-g | -39.7280 Percent change | Standard Error 62.7207 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | Eotaxin | 2.8770 Percent change | Standard Error 31.7644 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | G-CSF | -4.4567 Percent change | Standard Error 30.0457 |
| Itraconazole | Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment | GM-CSF | -45.6701 Percent change | Standard Error 60.284 |
Secondary
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)
Population: This was not feasible with the available tissue samples and hence data not collected.
Secondary
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)
Population: This was initially planned and did not collect data for this and did not assess.