Clinical trial NCT02357836: Neoadjuvant Itraconazole in Non-small Cell Lung Cancer
Official title: Phase 0 Pharmacodynamic Study of the Effects of Itraconazole on Tumor Angiogenesis and the Hedgehog Pathway in Early-stage Non-small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Non-small Cell Lung Cancer
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2015-02-06
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Changes in Tumor Tissue Microvessel Density [MVD] From Baseline
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Secondary outcomes:
measure: Change in HIF1α From Baseline
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Change in VEGFR2 From Baseline
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Change in Phospho-VEGFR2 From Baseline
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Mean Percent Change in Other Plasma Cytokine From Baseline to Post-Treatment
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Mean Percent Change in Angiogenic Cytokines From Baseline
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Changes in Perfusion (Ktrans)
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Number of Participants With Tumor SMO (Smoothened) Gene Mutations, GLI2 and CCND1 Copy Number, PI3K-mTOR Pathway Activation
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Change in Tumor Tissue GLI1, SHH and PTCH1 Levels From Baseline
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Change in Skin Biopsy GLI1 Levels From Baseline
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Change in Skin Biopsy SHH Levels From Baseline
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Change in Skin Biopsy PTCH1 Levels From Baseline
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Number of Participants With Tumor Cell Proliferation/Apoptosis
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Itraconazole Levels in Post-treatment Serum
timeFrame: Post Treatment (after 7-10 days of itraconazole bid)
measure: Itraconazole Levels in Tumor Tissue
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
measure: Itraconazole Levels in Skin Biopsy
timeFrame: Baseline and Post Treatment (after 7-10 days of itraconazole bid)
Other outcomes:
Locations:
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center
name: Lorraine Pelosof, M.D.
role: PRINCIPAL_INVESTIGATOR
References: