Neoadjuvant Itraconazole in 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.

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 0-2 performance status

5. Adequate organ function as defined below:

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(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 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 < 45 mL/min (increased risk of nephrogenic systemic fibrosis [NSF] from MRI
Gadolinium contrast).

12. Known allergy to MRI contrast.