Conditions: Non-Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 42
Healthy volunteers: no

Brief summary:
The current understanding of PR104 justifies the evaluation of PR104 with docetaxel in subjects with Non Small Cell Lung Cancer (NSCLC). These include:

* Aldo-keto reductase 1C3 (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 positron emission tomography (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 Granulocyte Colony-stimulating Factor (G-CSF) have been combined in a prior phase I study. A Maximum Tolerated Dose (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-fluoromisonidazole (18F-MISO) PET imaging
* Collect diagnostic biopsy samples for the determination of AKR1C3
* Collect plasma samples for assessment of potential biomarkers of tumor hypoxia

Detailed description:
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 fluoromisonidazole (F18-FMISO) and Fludeoxyglucose (FDG) for assessment of hypoxia and glucose metabolism, and pharmacokinetics of PR104.

Subjects will be randomized between arm 1 consisting of docetaxel, 75 mg/m\^2, administered intravenously (IV), every 21 days (an approved dose and schedule) and arm 2 consisting of docetaxel, 60 mg/m\^2 with PR104 at 770 mg/m\^2, 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.

Arms:
arm 1: Subjects randomized to the docetaxel arm will be administered 75 mg/m\^2, IV, every 21 days (an approved dose and schedule) arm 2: Subjects randomized to the PR104/docetaxel arm will be administered 60 mg/m\^2 docetaxel, IV, every 21 days plus 770 mg/m\^2 PR104, IV, every 21 days and prophylactic G-CSF.

Interventions: intervention 1: PR104 intervention 2: docetaxel intervention 3: docetaxel intervention 4: Granulocyte colony-stimulating factor
Intervention descriptions: intervention 1: 770 mg/m\^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops. intervention 2: 75 mg/m\^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops. intervention 3: 60 mg/m\^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops. intervention 4: Subjects randomized to PR104/docetaxel will receive prophylactic G-CSF per package insert administration recommendations. Number of Cycles: until progression or unacceptable toxicity develops.

Protocol document: