The current understanding of PR104 justifies the evaluation of PR104 with docetaxel in subjects with NSCLC. These include:

• AKR1C3. NSCLC has been shown to express high levels of AKR1C3 in about one half of tumors tested. Subjects with high levels of AKR1C3 should have increased activation of PR104 within their tumor.
• Hypoxia. NSCLC has been demonstrated to be a tumor with hypoxia based on both direct tumor measurements (oxygen electrodes) and hypoxic PET imaging. Tumor hypoxia in NSCLC should be sufficient to activate PR104 to its active metabolites PR104H and PR104M.
• Preclinical data. The use of docetaxel and PR104 alone and in combination in preclinical models demonstrates activity of PR104 as a single agent and supraadditive activity when PR104 and docetaxel are used in combination.
• Manageable toxicity. PR104 and docetaxel with G-CSF have been combined in a prior phase I study. An MTD has been identified and the major toxicities of this combination are understood. The current study will provide an estimate of the activity of PR104 in subjects with NSCLC.

This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in NSCLC to warrant a larger phase III registration study in this indication.

Primary objectives

• Estimate the response rate (RR) of PR104/docetaxel

Secondary objectives

• Evaluate survival
• Evaluate progression free survival (PFS)
• Evaluate time to progression (TTP)
• Evaluate safety
• Evaluate the pharmacokinetics of PR104 and its metabolites
• Evaluate the pharmacokinetics of docetaxel
• Evaluate the tumor hypoxia using 18F-MISO PET imaging
• Collect diagnostic biopsy samples for the determination of aldo-keto reductase 1C3
• Collect plasma samples for assessment of potential biomarkers of tumor hypoxia

A randomized phase II, multi-center, open-label, study of docetaxel versus docetaxel/PR104.

Following informed consent, subjects will undergo baseline evaluation with history, physical exams, blood work and disease assessment. Selected subjects will undergo PET imaging with F18-FMISO and FDG for assessment of hypoxia and glucose metabolism, and pharmacokinetics of PR104.

Subjects will be randomized between arm 1 consisting of docetaxel, 75 mg/m2, IV, every 21 days (an approved dose and schedule) and arm 2 consisting of docetaxel, 60 mg/m2 with PR104 at 770 mg/m2, IV, every 21 days. Subjects randomized to PR104/docetaxel will receive prophylactic G-CSF. One cycle will be 21 days in duration. Subjects will be evaluated weekly. A disease assessment will be performed every six weeks. Subjects with progression will be removed from study. Subjects with a response or stable disease may continue on study if this is considered beneficial by their physician.

• Drug: PR104
• Drug: docetaxel

Inclusion Criteria:

• Subjects with locally advanced or metastatic NSCLC (stage IIIb/IV) who have relapsed following adjuvant or first line therapy with a platinum containing regimen, and are appropriate candidates for treatment with single agent docetaxel
• Confirmed NSCLC by prior pathological analysis (tissue aspirate or biopsy)
• At least 21 days from prior chemotherapy
• At least 30 days from prior irradiation therapy
• ECOG Performance Status of 0 or 1
• Life expectancy of 12 weeks or more
• Adequate hematologic function (ANC ≥ 1.5 x 109/L; platelet count ≥100x109/L; hemoglobin ≥8.5 g /dL maintained in the absence of red blood cell transfusions; and prothrombin time international normalized ratio ≤1.7; or prothrombin time ≤2 seconds above control)
• Adequate hepatic function (albumin ≥2.8 g/dL; total bilirubin ≤2 mg/dL [51.3 μmol/L]; and alanine aminotransferase and aspartate aminotransferase ≤1.5 times the upper limit of the normal range)
• Adequate renal function (serum creatinine ≤2.0 times the upper limit of the normal range or creatinine clearance ≥60 mL/min).
• At least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (RECIST)

Exclusion Criteria:

• Previous treatment with docetaxel (prior treatment with paclitaxel permitted)
• Receipt of more than one prior systemic chemotherapy regimen
• Active concomitant malignancy likely to effect any of the primary or secondary outcome measures in the current study
• Women who are pregnant, breast-feeding or planning to become pregnant during the study
• Men or women of reproductive-potential who are unwilling to use an effective method of contraception during the study and for 30 days following the last dose
• Evidence of a significant medical disorder or laboratory finding that, in the opinion of the Investigator, compromises the subject's safety during study participation
• Active CNS metastatic disease requiring intervention
• Less than 4 weeks since major surgery
• Known HIV positivity