Phase II Study of Itraconazole and Pemetrexed in Patients With Previously Treated Non-Squamous NSCLC

Primary Objective

To evaluate the 3-month event-free survival of the combination of the combination of
itraconazole and pemetrexed in patients with recurrent/refractory non-small cell lung cancer.
3-month event-free survival (EFS) is defined as the proportion of patients who are alive and
without event after 3 months (evaluated in a window of +/- 1 week) of treatment. Events are
defined as disease progression or death from any cause. All patients treated on protocol will
be included in the determination of EFS, regardless of treatment modification or
discontinuation.

Secondary Objectives

To determine the objective response rate of the combination of itraconazole and pemetrexed in
patients with recurrent/refractory non-small cell lung cancer. The best overall response is
the best response recorded from the start of the treatment until disease
progression/recurrence (taking as reference for progressive disease the smallest measurements
recorded since the treatment started). The patient's best response assignment will depend on
the achievement of both measurement and confirmation criteria.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed NSCLC.

- Patient must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >20
mm with conventional techniques or as >10 mm with spiral CT scan. See Section 11 for
the evaluation of measurable and non-measurable disease.

- Patients must have received at least one previous chemotherapy regimen and have
recurrent or refractory disease.

- Age >18 years. Because no dosing or adverse event data are currently available on the
use of itraconazole in combination with pemetrexed in patients < 18 years of age, such
patients are excluded from this study but will be eligible for future pediatric phase
2 combination trials.

- Life expectancy of greater than 12 weeks.

- ECOG performance status < 2 (Karnofsky > 60%; see Appendix A).

- Patients must have normal organ and marrow function as defined below:

- leukocyte > 3,000/mcL

- absolute neutrophil count > 1,500/mcL

- platelets > 100,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT)< 2.5 X institutional upper limit of normal

- creatinine within normal institutional limits

- creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels
above institutional normal

- 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 and for
the duration of study participation. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 2 weeks earlier.

- Patients may not be receiving any other investigational agents.

- Patients who have received prior pemetrexed chemotherapy.

- Patients with uncontrolled brain metastases. Patients with brain metastases must have
stable neurologic status following local therapy (surgery or radiation) for at least 2
weeks, and must be without neurologic dysfunction that would confound the evaluation
of neurologic and other adverse events.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to itraconazole and pemetrexed or other agents used in the study.

- Itraconazole is a strong CYP3A4 inhibitor and may increase plasma concentrations of
drugs metabolized by this pathway. Coadministration of cisapride, midazolam, pimozide,
quinidine, lovastatin, simvastatin, triazolam, dofetilide, or levacetylmethadol
(levomethadyl) with itraconazole is contraindicated. Patients who take any of these
medications and who are not able to change to an alternative medication will be
excluded. Lists including medications and substances known or with the potential to
interact with the CYP3A4 isoenzymes are provided in Section 7.1.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because itraconazole and pemetrexed are
Class C and D agents, respectively, with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with itraconazole and
pemetrexed, breastfeeding should be discontinued if the mother is treated with
itraconazole or pemetrexed. These potential risks may also apply to other agents used
in this study.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with itraconazole or pemetrexed. In
addition, these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.