Comparative Trial of Pivanex and Docetaxel Vs Docetaxel Monotherapy in Patients With Advanced Non-Small Cell Lung Cancer

Rationale: Pivanex is a histone deacetylase inhibitor that induces tumor differentiation and/or apoptosis. Pivanex has been well tolerated in clinical trials and has shown preliminary evidence of efficacy in patients with non-small cell lung cancer. Docetaxel is an approved drug for second-line treatment of non-small cell lung cancer. Preclinical studies indicate that the combination of Pivanex and docetaxel is synergistic.

Purpose: This open-label randomized trial will evaluate whether combination therapy with Pivanex and docetaxel provides clinical benefit over docetaxel alone in patients with chemotherapy resistant non-small cell lung cancer.

Objectives:

• Compare the survival of patients with non-small cell lung cancer treated with combination therapy with Pivanex and docetaxel vs. docetaxel alone
• Compare the time to disease progression, tumor responses, and safety profile of patients with non-small cell lung cancer treated with combination therapy with Pivanex and docetaxel vs. docetaxel alone

Outline: This is a randomized, open-label, multicenter study in patients with non-small cell lung cancer who have previously been treated with no more than one prior platinum containing chemotherapy regimen. Patients are stratified by ECOG performance status (0-1 vs. 2), response to prior platinum based chemotherapy (progression vs. CR/PR/SD) and prior taxane therapy (yes vs. no). Patients are randomized to 1 of 2 treatment arms.

• Arm A: Patients receive the combination of Pivanex intravenously on Days 1-3 and docetaxel intravenously on Day 4. Treatment repeats every 21 days until disease progression or treatment withdrawal.
• Arm B: Patients receive docetaxel intravenously on Day 1. Treatment repeats every 21 days until disease progression or treatment withdrawal.

Inclusion criteria

• Histologically or cytologically confirmed non-small cell lung cancer (NSCLC); Treatment with one prior platinum-based chemotherapy regimen (Eligible patients may include:

• Patients previously treated with adjuvant or neoadjuvant chemotherapy (must be completed within 6 months prior to randomization) or
• Patients who have received chemotherapy for advanced or metastatic lung cancer);
• Recurrent or progressive NSCLC (local, distant, or both) following initial chemotherapy);
• Measurable or non-measurable disease;
• Males and females, age => 18 years;
• Adequate renal function with creatinine => 1.5 mg/dl;
• Adequate liver function with alkaline phosphatase => 2.5 X upper limit of normal, SGOT, and SGPT => 1.5 X upper limit of normal; and total bilirubin => upper limit of normal;
• Adequate bone marrow function: platelets > 100,000/mm3, hemoglobin => 9 g/dL, and absolute neutrophil count (ANC) => 1,500 cells/mm3;
• Able to give informed consent;
• Discontinuation of previous surgery, radiation therapy or cancer chemotherapy at least four weeks prior to randomization (six weeks if a prior nitrosourea or mitomycin C), with recovery from treatment-associated toxicity;
• A predicted life expectancy of at least 12 weeks; and
• ECOG performance status of 0, 1, or 2.

Exclusion criteria

• Receipt of more than one chemotherapy regimen for NSCLC;
• A second malignancy within the last 5 years other than curatively treated carcinoma-in-situ or non-melanoma skin cancer;
• Pregnant or lactating females (Females of childbearing potential must have a negative pregnancy test and all male and female patients of reproductive potential must agree to use adequate birth control);
• Known HIV-positive patients;
• Acute medical problems, such as ischemic heart or lung disease or uncontrolled systemic infection;
• Patients with any underlying medical conditions or circumstance, which would contraindicate therapy with study treatment, affect compliance or impair evaluation of study endpoints;
• Patients receiving investigational agents within 30 days of the screening visit;
• Known allergy to reagents in the study;
• Prior docetaxel therapy;
• Symptomatic or untreated brain metastases (Patients with brain metastases are eligible if they are clinically and neurologically stable for > 4 weeks since therapy (radiation therapy, radiosurgery/gamma knife; surgical resection) as determined by the investigator and either off corticosteroids or on a stable dose of corticosteroids).