A Randomized Phase II Study of SUBATM-itraconazole in Patients With Untreated Squamous NSCLC.

Study Overview
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Brief Summary
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Response rates. Changes in tumor blood flow.

Detailed Description
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To determine the objective response rates of cisplatin and gemcitabine with or without SUBATM-itraconazole in patients with chemotherapy-naïve metastatic squamous non-small cell lung cancer. To assess the changes in tumor blood flow as measured by contrast enhanced MRI scanning in patients with metastatic squamous non-small cell lung cancer treated with cisplatin and gemcitabine with or without SUBATM-itraconazole.

Official Title
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A Randomized Phase II Study of SUBATM-itraconazole With Cisplatin/Gemcitabine in Patients With Previously Untreated Metastatic Squamous Non-Small Cell Lung Cancer.

Conditions
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Non-small Cell Lung Cancer Metastatic

Intervention / Treatment
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* Drug: Cisplatin + Gemcitabine with SUBATM-itraconazole
* Drug: Cisplatin + Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage IV squamous cell lung cancer, with no prior systemic chemotherapy. Patients who have received prior adjuvant chemotherapy for early-stage lung cancer are eligible if at least 6 months have elapsed from completion of that treatment. Patients whose tumors contain mixed non-small cell histologies are eligible if squamous carcinoma is the predominant histology. Mixed tumors with small cell anaplastic elements are not eligible. Patient must have measurable disease per RECIST 1.1 (defined in section 9.1.2). Patients with previous radiotherapy as definitive therapy for locally advanced non-small cell lung cancer are eligible, as long as the recurrence is outside the original radiation therapy port. Radiation therapy must have been completed greater than or equal to 2 weeks prior to enroll in this study. Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of itraconazole or SUBATM-itraconazole in combination with gemcitabine/cisplatin in patients under 18 years of age, such patients are excluded from this study. Squamous cell lung cancer is exceedingly rare in children. Life expectancy of at least 12 weeks. Eastern Cooperative Oncology Group performance status 0 - 1. Patients must have adequate organ and marrow function. 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: Prior treatment with gemcitabine, cisplatin (except in the adjuvant setting), itraconazole or SUBATM-itraconazole. 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, SUBATM-itraconazole, gemcitabine, cisplatin or other agents used in the study. Itraconazole is a strong CYP3A4 inhibitor and may increase plasma concentrations of drugs metabolized by this pathway. Co-administration of cisapride, midazolam, pimozide, quinidine, lovastatin, simvastatin, triazolam, dofetilide, or levacetylmethadol (levomethadyl) with SUBATM-itraconazole or itraconazole is contraindicated. 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 is Class C agent and both gemcitabine and cisplatin are Class D agents, 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 SUBATM-itraconazole and gemcitabine/cisplatin, breastfeeding should be discontinued if the mother is to be treated on this protocol. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with SUBATM-itraconazole, gemcitabine, or cisplatin with these essential mediations. Medical contra-indication to MRI (e.g. gadolinium allergy, or severe claustrophobia).

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 |
| --- | --- |
| Experimental: Cisplatin + Gemcitabine with SUBATM-itraconazole<br>SUBATM-itraconazole 200 mg BID, Cisplatin 75 mg/m2 day 1, Gemcitabine 1000 mg/m2 days 1 + 8 for 6 cycles. Then SUBATM-itraconazole 200 mg BID alone. | Drug: Cisplatin + Gemcitabine with SUBATM-itraconazole<br>* Experimental Arm<br>* Other names: SUBATM-itraconazole + Cisplatin and Gemcitabine for 6 cycles followed by SUBATM-itraconazole alone.;|
| Active Comparator: Cisplatin + Gemcitabine<br>Arm B = Cisplatin 75 mg/m2 day 1, Gemcitabine 1000 mg/m2 days 1 + 8 for 6 cycles. Then Best supportive care. | Drug: Cisplatin + Gemcitabine<br>* Active Comparator<br>* Other names: Cisplatin and Gemcitabine for 6 cyles followed by Best supportive care.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rates | Per response evaluation criteria in solid tumors criteria | 6 weeks | 
| Tumor Blood Flow. | To assess the changes in tumor blood flow as measured by contrast enhanced MRI scanning in patients with metastatic squamous non-small cell lung cancer treated with cisplatin and gemcitabine with or without SUBATM-itraconazole. | 6 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Progression | To determine the median time to progression and median duration of survival of patients with metastatic squamous non-small cell lung cancer treated with cisplatin and gemcitabine with or without SUBATM-itraconazole. | 2 years. | 
| Adverse Effects | To characterize the adverse effects of cisplatin and gemcitabine with or without SUBATM-itraconazole in this patient population. | 2 years. | 
| Itraconazole Exposure Parameters | To correlate itraconazole exposure parameters with median time to progression and median survival in this patient population. | 2 years. | 
| Tumor Necrosis | To assess changes in tumor necrosis in response to cisplatin and gemcitabine with or without SUBATM-itraconazole. | 2 years. |