Randomized, Multi-center, Open-label, Study of PR104 Versus PR104/Docetaxel in Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Phase II, Multi-Center, Open-Label Trial of PR104 and Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: PR104
* Drug: docetaxel
* Drug: docetaxel
* Drug: Granulocyte colony-stimulating factor


Participation Criteria
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Eligibility Criteria
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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 Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Life expectancy of 12 weeks or more Adequate hematologic function [Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; platelet count ≥100x10^9/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 Central Nervous System (CNS) metastatic disease requiring intervention Less than 4 weeks since major surgery Known human immunodeficiency virus (HIV) positivity

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: Docetaxel 75 mg/m^2<br>Subjects randomized to the docetaxel arm will be administered 75 mg/m^2, IV, every 21 days (an approved dose and schedule) | Drug: docetaxel<br>* 75 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.<br>* Other names: Taxotere;|
| Experimental: PR104 + 60 mg/m^2 docetaxel<br>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. | Drug: PR104<br>* 770 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.<br>Drug: docetaxel<br>* 60 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.<br>* Other names: Taxotere;Drug: Granulocyte colony-stimulating factor<br>* Subjects randomized to PR104/docetaxel will receive prophylactic G-CSF per package insert administration recommendations. Number of Cycles: until progression or unacceptable toxicity develops.<br>* Other names: GCSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Achieved a Response (Complete or Partial) After Receiving PR104/Docetaxel Versus Docetaxel Alone | Defined as the number of subjects with complete response (CR) or partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria | Participants were followed for the duration on study, an average of 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability: Serious Adverse Events | The number of participants with at least one Serious Adverse Event was measured. | 30 days following last administration of study treatment | 
| Positive Aldo-keto Reductase 1C3 (AKR1C3) Expression in Participating Patients | AKR1C3 was evaluated on a semi-quantitative scale, and the percentage of cells staining at each of the following four levels was recorded: 0 (unstained), 1+ (weak staining), 2+ (moderate staining) and 3+ (strong staining). Patients with a strong staining score (3+) were considered to be AKR1C3 positive | Within 1 year of enrollment |