This is a non-randomized, single-arm, single-institution, open label, two-stage phase II and dose-ranging study designed to evaluate the efficacy and safety of paclitaxel poliglumex in combination with pemetrexed in patients with advanced stage IIIB or stage IV NSCLC.

Primary objective

To evaluate the overall response rate (complete plus partial responses by RECIST criteria) to the combination of paclitaxel poliglumex and pemetrexed as therapy in patients with advanced NSCLC.

Secondary Objectives

To evaluate the safety and adverse event profile of the combination of paclitaxel poliglumex and pemetrexed as therapy in patients with advanced NSCLC.

To evaluate the duration of response, time to progression, and overall survival of advanced NSCLC treated with the combination of paclitaxel poliglumex and pemetrexed.

To compare the overall response rate using three-dimensional reconstruction of target lesions by Medical Metrx Solutions (MMS) and RECIST criteria.

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of locally advanced and/or metastatic NSCLC (Stage IIIB or IV).
• Bidimensionally measurable lesions or unidimensionally evaluable lesions.
• Age ≥ 18 years.
• At least one measurable target lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST), which has not been previously treated with local therapy (e.g. radiation therapy, chemoembolization, surgery, etc.).
• May have received prior chemotherapy (including taxanes) for advanced NSCLC.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Life expectancy > 12 weeks.
• No active infections.
• Adequate liver and bone marrow function.
• AST<2.5 x ULN, bilirubin <1.5x ULN, alkaline phosphatase<2.5 x ULN (unless bone origin and no liver metastases are documented).
• ANC ≥ 1,500/uL, platelet count ≥ 100,000/uL.
• Normal PT and PTT.
• Bisphosphates initiated prior to study entry will be permitted. However, initiation of bisphosphonates following study entry is not permitted.
• Patients with treated brain metastases must be neurologically stable.
• At least 3 weeks since last chemotherapy and recovered from treatment-related adverse events ≤ grade 1.
• At least 3 weeks since prior radiation and recovered from treatment-related adverse events ≤ grade 1.
• Women of childbearing potential are eligible for the study, provided they have a negative serum or urine pregnancy test within three days of study entry, and an adequate method of contraception is used. Acceptable methods of birth control include barrier methods (condoms, diaphragms with spermicide) or intrauterine devices (IUD). Women whose sole sexual partner is infertile, or who are not sexually active, are also eligible.
• Able to provide written informed consent.

Exclusion Criteria:

• Grade 2 or greater peripheral neuropathy, according to the National Cancer Institute-Common Toxicity Criteria.
• Clinically significant pleural, pericardial or abdominal effusions.
• Untreated brain metastases.
• Patients with previously diagnosed brain metastases will be eligible if they are neurologically stable and have recovered from the effects of radiotherapy or surgery (≤ grade 2).
• Patients with brain metastases must have at least one other site of measurable disease.
• Concurrent radiotherapy.
• Other concurrent cancer treatment-related investigational agent. Investigational supportive care medications are permitted.
• Concurrent treatment with unfractionated heparin or warfarin.
• History of radiotherapy encompassing greater than 50% of the marrow-bearing skeleton.
• Prior bone marrow or stem cell transplant.
• History of other active malignancy within the last year requiring chemotherapy, not including curatively-treated carcinoma in situ of the cervix, or non-melanoma skin cancer (basal cell carcinoma or squamous cell carcinoma).
• Uncontrolled infection.
• Active bleeding, or history of bleeding requiring transfusion within 2 weeks of study entry.
• Active cardiac disease, as defined as:
• Current history of uncontrolled or symptomatic angina.
• History of arrhythmias requiring medications or clinically significant arrhythmias, with the exception of uncomplicated atrial fibrillation.
• Myocardial infarction < 6 months from study entry.
• Any other cardiac conditions, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.