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

Study Overview
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Brief Summary
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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. 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.

Detailed Description
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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.

Official Title
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A Randomized Phase II Study of Itraconazole and Pemetrexed in Patients With Previously Treated Non-Squamous Non-Small Cell Lung Cancer

Conditions
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Recurrent Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Itraconazole
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Itraconazole with Pemetrexed<br>Pemetrexed IV every 21 days with oral Itraconazole 200mg daily. | Drug: Itraconazole<br>* Itraconazole 200 mg once daily<br>* Other names: Sporanox;Drug: Pemetrexed<br>* Pemetrexed every 21 days.<br>* Other names: Alimta;|
| Active Comparator: Single agent pemetrexed<br>Pemetrexed IV on day 1 of 21-day cycle. | Drug: Pemetrexed<br>* Pemetrexed every 21 days.<br>* Other names: Alimta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Median number of days alive | up to 3 years | 
| Progression Free Survival as Measured by Number of Days Without Disease Progression |  | 1 year | 
| RECIST Response | Number of participants with partial response (PR), stable disease (SD) and progressive disease (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Blood Flow | Tumor blood flow activity in patients with previously treated non-squamous non-small cell lung cancer receiving pemetrexed alone or pemetrexed plus itraconazole. | 3 years | 
| Tumor Metabolic Activity | Tumor metabolic activity in patients with previously treated non-squamous non-small cell lung cancer receiving pemetrexed alone or pemetrexed plus itraconazole. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent Non-Small Cell Lung Cancer